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• W1949272583 abstract "BCL-2 family interactions are mediated by evolutionarily diverse BH3 motifs to regulate apoptosis. Given their key roles, BH3 mimetics are in clinical trials as cancer therapies. The discovery of novel BH3-only proteins represents a major endeavor in the cell death field. As a result, BH3 motifs are reportedly present in a nebulous conglomerate of different proteins, both structured and intrinsically disordered. There is no rigorous definition of a BH3 motif. Currently available BH3 signatures are diverse and elusive for predicting new functional BH3-containing proteins. Redefining the BH3 motif as a new type of short linear motif (SLiM) or molecular recognition feature (MoRF) reconciles many puzzling features of this motif and opens up new avenues for research. B cell lymphoma-2 (BCL-2)-related proteins control programmed cell death through a complex network of protein–protein interactions mediated by BCL-2 homology 3 (BH3) domains. Given their roles as dynamic linchpins, the discovery of novel BH3-containing proteins has attracted considerable attention. However, without a clearly defined BH3 signature sequence the BCL-2 family has expanded to include a nebulous group of nonhomologous BH3-only proteins, now justified by an intriguing twist. We present evidence that BH3s from both ordered and disordered proteins represent a new class of short linear motifs (SLiMs) or molecular recognition features (MoRFs) and are diverse in their evolutionary histories. The implied corollaries are that BH3s have a broad phylogenetic distribution and could potentially bind to non-BCL-2-like structural domains with distinct functions. B cell lymphoma-2 (BCL-2)-related proteins control programmed cell death through a complex network of protein–protein interactions mediated by BCL-2 homology 3 (BH3) domains. Given their roles as dynamic linchpins, the discovery of novel BH3-containing proteins has attracted considerable attention. However, without a clearly defined BH3 signature sequence the BCL-2 family has expanded to include a nebulous group of nonhomologous BH3-only proteins, now justified by an intriguing twist. We present evidence that BH3s from both ordered and disordered proteins represent a new class of short linear motifs (SLiMs) or molecular recognition features (MoRFs) and are diverse in their evolutionary histories. The implied corollaries are that BH3s have a broad phylogenetic distribution and could potentially bind to non-BCL-2-like structural domains with distinct functions. BCL-2 is the founding member of a group of proteins that regulate apoptotic (programmed) cell death, mitochondrial physiology, and probably other cellular processes [1Czabotar P.E. et al.Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nat. Rev. Mol. Cell Biol. 2014; 15: 49-63Crossref PubMed Scopus (2272) Google Scholar, 2Hardwick J.M. Soane L. Multiple functions of BCL-2 family proteins.Cold Spring Harb. Perspect. Biol. 2013; 5: a008722Crossref PubMed Scopus (422) Google Scholar]. This protein group has two main subgroups that share a single sequence motif commonly known as the BH3. The first subgroup comprises a family of homologs related by common ancestry to BCL-2. The second subgroup contains the so-called BH3-only proteins, which are apparently unrelated evolutionarily and structurally to each other and to BCL-2 homologs. Current models of apoptosis regulation exclusively focus on these two subgroups, while ignoring a third, larger collection of even more diverse BH3-containing proteins. The biological impact of this third group and how it integrates into the BCL-2 network is poorly studied, in part because the definition of a BH3 is sketchy. Here we present arguments that BH3s represent a new class of SLiMs. Defining the BH3 in this way relieves constraints on 3D structure requirements and reconciles its many puzzling features. By interpreting the BH3 as a linear sequence motif also provides clues about the emergence of a sophisticated BCL-2-regulated apoptotic pathway in multicellular animals. Rather than seeking to define a subset of true BH3s among the published candidates, this new view broadens the realm of potentially druggable interactions between a BH3 and its target. BCL-2-homologous proteins share up to four different BH motifs (BH1–BH4) that are located within a single structural domain, a uniquely folded α-helical bundle. Although many details remain unresolved, BCL-2 homologs are either antiapoptotic (e.g., BCL-2, BCL-xL) or proapoptotic (e.g., BAX, BAK), whereas all eight canonical BH3-only proteins (e.g., BIM, BAD) promote apoptosis after a cell death stimulus. BH3-only proteins have a single region of sequence similarity (see Glossary) with BCL-2, termed the BH3 domain. However, because the BH3 does not fit the criteria for a protein ‘domain’, we refer to the BH3 as a motif rather than a domain. The BH3 motif is present in an α-helical structure but the linear primary sequence signature of the BH3 motif is not conclusively defined [3Aouacheria A. et al.Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-only, and BNip families of apoptotic regulators.Mol. Biol. Evol. 2005; 22: 2395-2416Crossref PubMed Scopus (102) Google Scholar, 4Aouacheria A. et al.Evolution of Bcl-2 homology motifs: homology versus homoplasy.Trends Cell Biol. 2013; 23: 103-111Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5Kvansakul M. Hinds M.G. The structural biology of BH3-only proteins.Methods Enzymol. 2014; 544: 49-74Crossref PubMed Scopus (42) Google Scholar, 6Shamas-Din A. et al.BH3-only proteins: orchestrators of apoptosis.Biochim. Biophys. Acta. 2011; 1813: 508-520Crossref PubMed Scopus (264) Google Scholar]. The eight canonical BH3-only proteins are further divided into two functional groups, the direct activators and the sensitizers of cell death [7Letai A. et al.Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.Cancer Cell. 2002; 2: 183-192Abstract Full Text Full Text PDF PubMed Scopus (1378) Google Scholar, 8Kim H. et al.Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.Nat. Cell Biol. 2006; 8: 1348-1358Crossref PubMed Scopus (712) Google Scholar, 9Moldoveanu T. et al.BID-induced structural changes in BAK promote apoptosis.Nat. Struct. Mol. Biol. 2013; 20: 589-597Crossref PubMed Scopus (163) Google Scholar, 10Llambi F. et al.A unified model of mammalian BCL-2 protein family interactions at the mitochondria.Mol. Cell. 2011; 44: 517-531Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar]. Despite its critical role in regulating cell death, the BH3 sequence motif currently lacks a unifying definition and is suggested to occur in approximately 40 additional proteins belonging to different protein families, raising the question of whether the BH3 motif is definable [4Aouacheria A. et al.Evolution of Bcl-2 homology motifs: homology versus homoplasy.Trends Cell Biol. 2013; 23: 103-111Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 11DeBartolo J. et al.Genome-wide prediction and validation of peptides that bind human prosurvival Bcl-2 proteins.PLoS Comput. Biol. 2014; 10: e1003693Crossref PubMed Scopus (28) Google Scholar]. Through a systems-biology lens, the mitochondrial checkpoint of apoptosis comprises a network of highly connected and mutually communicating proteins. In this view, the integration of diverse BH3-only proteins into the BCL-2 network imposes an organized hierarchy with a kite-shaped architecture that is recognizable as a form of bowtie-configured network (Figure 1A) . Many robust biological systems share this bowtie (or hourglass) structure in which a central hub (formed here by the BCL-2 homologs) receives and integrates diverse inputs from a signal-processing layer (BH3-only proteins; the kite surfers) to generate one or more outputs (in this case a binary switch: mitochondrial integrity vs mitochondrial permeabilization and death). Consistent with this model, evidence suggests that BH3-only proteins are sentinels that communicate the status of diverse cellular processes to the effector BCL-2-homologous proteins (reviewed in [12Moldoveanu T. et al.Many players in BCL-2 family affairs.Trends Biochem. Sci. 2014; 39: 101-111Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 13Westphal D. et al.Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis.Cell Death Differ. 2014; 21: 196-205Crossref PubMed Scopus (281) Google Scholar]). This network structure ensures appropriate responses to multiple signaling pathways and cell stresses to determine cell death. Within this bowtie network, the binding interactions of BH3 motifs are the most extensively characterized because of their clinical relevance to diagnostics and therapeutics. The search for small molecules that mimic the biological effects of BH3 motifs enabled the identification of one of the first druggable protein–protein interaction interfaces [14Petros A.M. et al.Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.Protein Sci. 2000; 9: 2528-2534Crossref PubMed Scopus (375) Google Scholar]. The BH3 mimetics ABT-737 and ABT-199 bind in the hydrophobic BH3-binding groove on the surface of antiapoptotic BCL-xL and/or BCL-2 to kill cancer cells [15Davids M.S. Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer.J. Clin. Oncol. 2012; 30: 3127-3135Crossref PubMed Scopus (223) Google Scholar] (Box 1). However, despite having many high-resolution structures of BH3-bound complexes and extensive mutagenesis data to identify critical residues at the interface of both the BH3 and its binding partners [11DeBartolo J. et al.Genome-wide prediction and validation of peptides that bind human prosurvival Bcl-2 proteins.PLoS Comput. Biol. 2014; 10: e1003693Crossref PubMed Scopus (28) Google Scholar, 16Czabotar P.E. et al.Mutation to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis.J. Biol. Chem. 2011; 286: 7123-7131Crossref PubMed Scopus (95) Google Scholar, 17DeBartolo J. et al.Predictive Bcl-2 family binding models rooted in experiment or structure.J. Mol. Biol. 2012; 422: 124-144Crossref PubMed Scopus (41) Google Scholar, 18Lee E.F. et al.The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains.J. Biol. Chem. 2014; 289: 36001-36017Crossref PubMed Scopus (31) Google Scholar], the available studies have not exhaustively examined the full range of sequence variability observed in reported BH3 motifs. Without rigorous criteria to accurately predict or exclude candidate BH3-containing proteins, the persistent lumping together of nonhomologous proteins bearing putative BH3-like motifs (e.g., [19Brunelle J.K. Letai A. Control of mitochondrial apoptosis by the Bcl-2 family.J. Cell Sci. 2009; 122: 437-441Crossref PubMed Scopus (744) Google Scholar, 20Tait S.W. Green D.R. Mitochondria and cell death: outer membrane permeabilization and beyond.Nat. Rev. Mol. Cell Biol. 2010; 11: 621-632Crossref PubMed Scopus (1921) Google Scholar, 21Youle R.J. Strasser A. The BCL-2 protein family: opposing activities that mediate cell death.Nat. Rev. Mol. Cell Biol. 2008; 9: 47-59Crossref PubMed Scopus (3656) Google Scholar]) appears to defy logic. However, unforeseen logic may indeed prevail in this madness. Here we argue that BH3 motifs share most of the attributes of SLiMs and, more precisely, of those SLiMs that are associated with binding events (Box 2). Thus, BH3 motifs appear to represent a protein–protein interaction module of broader scope that spreads beyond even the extended BCL-2 family and potentially to non-metazoan organisms.Box 1BH3 Mimetics Have Therapeutic ValueThe BCL-2-regulated apoptotic pathway is a therapeutic target in degenerative disorders, infectious and immune diseases, and cancer [1Czabotar P.E. et al.Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nat. Rev. Mol. Cell Biol. 2014; 15: 49-63Crossref PubMed Scopus (2272) Google Scholar]. It was hypothesized over 15 years ago that BH3 mimetics, discovered through rational design or high-throughput screening, would induce cancer cell apoptosis by targeting antiapoptotic members. Consistently, cell-permeable peptides corresponding to BH3 motifs from BID or BAD were shown to induce apoptosis in BCL-2- or BCL-xL-expressing cells [14Petros A.M. et al.Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.Protein Sci. 2000; 9: 2528-2534Crossref PubMed Scopus (375) Google Scholar, 92Holinger E.P. et al.Bak BH3 peptides antagonize Bcl-xL function and induce apoptosis through cytochrome c-independent activation of caspases.J. Biol. Chem. 1999; 274: 13298-13304Crossref PubMed Scopus (248) Google Scholar]. Thereafter, synthetic small-molecule inhibitor drugs that bind a hydrophobic pocket on prosurvival BCL-2 proteins (Figure I) were identified and evaluated for their efficacy as cytotoxic agents used alone or in combination with conventional anticancer drugs. Several such high-affinity antagonists are at various stages of development, the orally bioavailable molecule ABT-199 (which selectively targets BCL-2) being currently in clinical trials with high expectations [93Roberts A.W. et al.Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies.Br. J. Haematol. 2015; 170: 669-678Crossref PubMed Scopus (77) Google Scholar]. Thus, a better appreciation of the complex interplay between the various blocks of BCL-2 proteins successfully identified one of the first α-helix-mediated protein–protein interaction target sites (with p53–hDM2) and demonstrated that affinity-based screening for small molecules mimicking the BH3 motif is a feasible strategy. As SLiMs, BH3 motifs may be found to interact with proteins that do not adopt the BCL-2 structural fold, as recently suggested [91Szlyk B. et al.A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.Nat. Struct. Mol. Biol. 2014; 21: 36-42Crossref PubMed Scopus (44) Google Scholar]. Future experiments will have to assess the druggability of such interactions and the potential need to increase the current arsenal of BH3 mimetics.Box 2What Are SLiMs?SLiMs/eukaryotic motifs (ELMs) are short, modular functional units of proteins, typically comprising a stretch of 3–11 contiguous amino acid residues with only three to five core positions conferring most of their binding specificity [41Van Roey K. et al.Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.Chem. Rev. 2014; 114: 6733-6778Crossref PubMed Scopus (274) Google Scholar, 81Diella F. et al.Understanding eukaryotic linear motifs and their role in cell signaling and regulation.Front. Biosci. 2008; 13: 6580-6603Crossref PubMed Google Scholar]. SLiMs serve as post-translational modification sites or ligands for other molecules (protein domains or nucleic acids) [35Puntervoll P. et al.ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins.Nucleic Acids Res. 2003; 31: 3625-3630Crossref PubMed Scopus (521) Google Scholar, 39Davey N.E. et al.Attributes of short linear motifs.Mol. Biosyst. 2012; 8: 268-281Crossref PubMed Scopus (409) Google Scholar, 40Tompa P. et al.A million peptide motifs for the molecular biologist.Mol. Cell. 2014; 55: 161-169Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 41Van Roey K. et al.Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.Chem. Rev. 2014; 114: 6733-6778Crossref PubMed Scopus (274) Google Scholar, 43Weatheritt R.J. Gibson T.J. Linear motifs: lost in (pre)translation.Trends Biochem. Sci. 2012; 37: 333-341Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 81Diella F. et al.Understanding eukaryotic linear motifs and their role in cell signaling and regulation.Front. Biosci. 2008; 13: 6580-6603Crossref PubMed Google Scholar]. Due to their short length, they constitute only a small binding surface area and engage in low-affinity, transient, and modulatable interactions, typically in the low-micromolar range. The best known examples are the binding motifs of typical modular protein–protein interaction domains such as the SH3, SH2, and PDZ domains and they are usually described by a short consensus sequence (also termed a ‘regular expression’; e.g., [P-X-X-P] for the SH3 domain-binding motif). Because the number of residues involved in the activity of motifs is very small, they exhibit high evolutionary plasticity, can be generated by a single point mutation, often arise de novo, and evolve convergently. Therefore, motifs are evolutionarily highly variable and are much less conserved than globular domains in the same sequences. SLiMs tend to occur in intrinsically disordered regions of proteins [42Fuxreiter M. et al.Local structural disorder imparts plasticity on linear motifs.Bioinformatics. 2007; 23: 950-956Crossref PubMed Scopus (344) Google Scholar, 43Weatheritt R.J. Gibson T.J. Linear motifs: lost in (pre)translation.Trends Biochem. Sci. 2012; 37: 333-341Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] and, owing to this fact, their distinction from MoRFs is not clear cut. MoRFs are on average longer than SLiMs and are defined on a structural basis (by their ability to fold on interacting with partners) rather than on a sequence basis [44Cumberworth A. et al.Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes.Biochem. J. 2013; 454: 361-369Crossref PubMed Scopus (135) Google Scholar, 45Mohan A. et al.Analysis of molecular recognition features (MoRFs).J. Mol. Biol. 2006; 362: 1043-1059Crossref PubMed Scopus (608) Google Scholar]. Due to their potential high density and evolutionary agility, SLiMs are thought to be actively involved in wiring and rewiring the connectivity of the interactome. Established motif instances are deposited in the ELM resource [55Dinkel H. et al.ELM – the database of eukaryotic linear motifs.Nucleic Acids Res. 2012; 40: D242-D251Crossref PubMed Scopus (254) Google Scholar], where their major functional classes are ligand binding (LIG), docking (DOC), degradation (DEG), targeting (TAR), cleavage (CLV), and post-translational modification (MOD). BCL-2 homologs have never been described before as proteins able to bind linear motifs, although the attributes of SLiMs clearly suggest that BH3 should be considered as such a motif. Although some amount of sequence variation is observed in the BH1 and BH2 motifs of BCL-2-homologous proteins, these regions are not SLiMs as they constitute the borders of the structural hairpin lying at the center of the BCL-2 helical bundle and form the hydrophobic receptor cleft essential for BH3 binding (rather than binding by themselves to a hydrophobic pocket). The BCL-2-regulated apoptotic pathway is a therapeutic target in degenerative disorders, infectious and immune diseases, and cancer [1Czabotar P.E. et al.Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nat. Rev. Mol. Cell Biol. 2014; 15: 49-63Crossref PubMed Scopus (2272) Google Scholar]. It was hypothesized over 15 years ago that BH3 mimetics, discovered through rational design or high-throughput screening, would induce cancer cell apoptosis by targeting antiapoptotic members. Consistently, cell-permeable peptides corresponding to BH3 motifs from BID or BAD were shown to induce apoptosis in BCL-2- or BCL-xL-expressing cells [14Petros A.M. et al.Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.Protein Sci. 2000; 9: 2528-2534Crossref PubMed Scopus (375) Google Scholar, 92Holinger E.P. et al.Bak BH3 peptides antagonize Bcl-xL function and induce apoptosis through cytochrome c-independent activation of caspases.J. Biol. Chem. 1999; 274: 13298-13304Crossref PubMed Scopus (248) Google Scholar]. Thereafter, synthetic small-molecule inhibitor drugs that bind a hydrophobic pocket on prosurvival BCL-2 proteins (Figure I) were identified and evaluated for their efficacy as cytotoxic agents used alone or in combination with conventional anticancer drugs. Several such high-affinity antagonists are at various stages of development, the orally bioavailable molecule ABT-199 (which selectively targets BCL-2) being currently in clinical trials with high expectations [93Roberts A.W. et al.Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies.Br. J. Haematol. 2015; 170: 669-678Crossref PubMed Scopus (77) Google Scholar]. Thus, a better appreciation of the complex interplay between the various blocks of BCL-2 proteins successfully identified one of the first α-helix-mediated protein–protein interaction target sites (with p53–hDM2) and demonstrated that affinity-based screening for small molecules mimicking the BH3 motif is a feasible strategy. As SLiMs, BH3 motifs may be found to interact with proteins that do not adopt the BCL-2 structural fold, as recently suggested [91Szlyk B. et al.A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.Nat. Struct. Mol. Biol. 2014; 21: 36-42Crossref PubMed Scopus (44) Google Scholar]. Future experiments will have to assess the druggability of such interactions and the potential need to increase the current arsenal of BH3 mimetics. SLiMs/eukaryotic motifs (ELMs) are short, modular functional units of proteins, typically comprising a stretch of 3–11 contiguous amino acid residues with only three to five core positions conferring most of their binding specificity [41Van Roey K. et al.Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.Chem. Rev. 2014; 114: 6733-6778Crossref PubMed Scopus (274) Google Scholar, 81Diella F. et al.Understanding eukaryotic linear motifs and their role in cell signaling and regulation.Front. Biosci. 2008; 13: 6580-6603Crossref PubMed Google Scholar]. SLiMs serve as post-translational modification sites or ligands for other molecules (protein domains or nucleic acids) [35Puntervoll P. et al.ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins.Nucleic Acids Res. 2003; 31: 3625-3630Crossref PubMed Scopus (521) Google Scholar, 39Davey N.E. et al.Attributes of short linear motifs.Mol. Biosyst. 2012; 8: 268-281Crossref PubMed Scopus (409) Google Scholar, 40Tompa P. et al.A million peptide motifs for the molecular biologist.Mol. Cell. 2014; 55: 161-169Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 41Van Roey K. et al.Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.Chem. Rev. 2014; 114: 6733-6778Crossref PubMed Scopus (274) Google Scholar, 43Weatheritt R.J. Gibson T.J. Linear motifs: lost in (pre)translation.Trends Biochem. Sci. 2012; 37: 333-341Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 81Diella F. et al.Understanding eukaryotic linear motifs and their role in cell signaling and regulation.Front. Biosci. 2008; 13: 6580-6603Crossref PubMed Google Scholar]. Due to their short length, they constitute only a small binding surface area and engage in low-affinity, transient, and modulatable interactions, typically in the low-micromolar range. The best known examples are the binding motifs of typical modular protein–protein interaction domains such as the SH3, SH2, and PDZ domains and they are usually described by a short consensus sequence (also termed a ‘regular expression’; e.g., [P-X-X-P] for the SH3 domain-binding motif). Because the number of residues involved in the activity of motifs is very small, they exhibit high evolutionary plasticity, can be generated by a single point mutation, often arise de novo, and evolve convergently. Therefore, motifs are evolutionarily highly variable and are much less conserved than globular domains in the same sequences. SLiMs tend to occur in intrinsically disordered regions of proteins [42Fuxreiter M. et al.Local structural disorder imparts plasticity on linear motifs.Bioinformatics. 2007; 23: 950-956Crossref PubMed Scopus (344) Google Scholar, 43Weatheritt R.J. Gibson T.J. Linear motifs: lost in (pre)translation.Trends Biochem. Sci. 2012; 37: 333-341Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] and, owing to this fact, their distinction from MoRFs is not clear cut. MoRFs are on average longer than SLiMs and are defined on a structural basis (by their ability to fold on interacting with partners) rather than on a sequence basis [44Cumberworth A. et al.Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes.Biochem. J. 2013; 454: 361-369Crossref PubMed Scopus (135) Google Scholar, 45Mohan A. et al.Analysis of molecular recognition features (MoRFs).J. Mol. Biol. 2006; 362: 1043-1059Crossref PubMed Scopus (608) Google Scholar]. Due to their potential high density and evolutionary agility, SLiMs are thought to be actively involved in wiring and rewiring the connectivity of the interactome. Established motif instances are deposited in the ELM resource [55Dinkel H. et al.ELM – the database of eukaryotic linear motifs.Nucleic Acids Res. 2012; 40: D242-D251Crossref PubMed Scopus (254) Google Scholar], where their major functional classes are ligand binding (LIG), docking (DOC), degradation (DEG), targeting (TAR), cleavage (CLV), and post-translational modification (MOD). BCL-2 homologs have never been described before as proteins able to bind linear motifs, although the attributes of SLiMs clearly suggest that BH3 should be considered as such a motif. Although some amount of sequence variation is observed in the BH1 and BH2 motifs of BCL-2-homologous proteins, these regions are not SLiMs as they constitute the borders of the structural hairpin lying at the center of the BCL-2 helical bundle and form the hydrophobic receptor cleft essential for BH3 binding (rather than binding by themselves to a hydrophobic pocket). The BH3 motif was originally defined in 1995 as a region of ∼7–15 amino acids with sequence similarity shared by the pro- and antideath BCL-2 homologs BAK, BAX, BCL-2, and BCL-xL plus a shorter, nonhomologous protein, BIK (reviewed in [5Kvansakul M. Hinds M.G. The structural biology of BH3-only proteins.Methods Enzymol. 2014; 544: 49-74Crossref PubMed Scopus (42) Google Scholar]). In the following 5 years, BH3 motifs were identified in additional proteins, eventually settling on the full repertoire of 14 BCL-2 homologs and eight canonical BH3-only proteins in humans (Table S1 in the supplementary material online) comprising four direct activators (BIM, PUMA, truncated tBID, and NOXA) and four sensitizers (BAD, BIK, BMF, and HRK) (Figure 1A). The eight BH3 motifs in these eight proteins were identified only on the basis of visual inspection of their sequences and were confirmed by experimental evidence of proapoptotic activity on binding to BCL-2 homologs. These proteins (plus worm EGL-1) constitute the canonical BH3-only subgroup. The opportunity to discover new BH3-only proteins is attractive given their roles as linchpins connecting the cellular interactome to the apoptosis checkpoint. However, computational approaches have not validated the BH3 sequence signature [4Aouacheria A. et al.Evolution of Bcl-2 homology motifs: homology versus homoplasy.Trends Cell Biol. 2013; 23: 103-111Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 22Hawley R.G. et al.An integrated bioinformatics and computational biology approach identifies new BH3-only protein candidates.Open Biol. J. 2012; 5: 6-16Crossref PubMed Scopus (11) Google Scholar, 23Kaczmarek K. et al.Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice.Mol. Biol. Cell. 2011; 22: 1766-1779Crossref PubMed Scopus (25) Google Scholar, 24Lee D.H. et al.Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy.Biochem. Biophys. Res. Commun. 2011; 408: 541-547Crossref PubMed Scopus (21) Google Scholar]. Most of the additional cellular and viral proteins claimed to contain functional BH3-like motifs belong to unrelated (non-BCL-2) protein families and are referred to here as ‘noncanonical’ BH3-containing proteins due to limited experimental data relative to the eight canonical BH3-only proteins included in the extended BCL-2 family (Figure S1 and Table S1 in the supplementary material online). The overwhelming majority of these noncanonical BH3-bearing proteins are sensitizer BH3s rather than direct activator BH3s because they trigger cell death by engaging prosurvival BCL-2 family members. Although most noncanonical BH3 motifs are untested for direct BAX/BAK activator function, exceptions have been reported [25Molouki A. et al.The matrix (M) protein of Newcastle disease virus binds to human bax through its BH3 domain.Virol. J. 2011; 8: 385Crossref PubMed Scopus (31) Google Scholar, 26Rodolfo C. et al.Tissue transglutaminase is a multifunctional BH3-only protein.J. Biol. Chem. 2004; 279: 54783-54792Crossref PubMed Scopus (85) Google Scholar, 27Tan K.O." @default.
• W1949272583 created "2016-06-24" @default.
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• W1949272583 date "2015-12-01" @default.
• W1949272583 modified "2023-10-06" @default.
• W1949272583 title "Redefining the BH3 Death Domain as a ‘Short Linear Motif’" @default.
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