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• W2159457776 abstract "•Genomic principles describing how disordered segments influence protein half-life•Proteins with terminal or internal disordered segments have a short half-life•The relationship is evolutionarily conserved between yeast, mouse, and human•Divergence in disordered segments after gene duplication impacts protein half-life Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences. Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences. IntroductionProtein degradation is the endpoint of gene expression, and correct turnover of proteins is essential for cellular function. Indeed, protein half-life impacts virtually all cellular processes including the cell cycle (Pagano et al., 1995Pagano M. Tam S.W. Theodoras A.M. Beer-Romero P. Del Sal G. Chau V. Yew P.R. Draetta G.F. Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27.Science. 1995; 269: 682-685Crossref PubMed Scopus (1734) Google Scholar), DNA repair (Lakin and Jackson, 1999Lakin N.D. Jackson S.P. Regulation of p53 in response to DNA damage.Oncogene. 1999; 18: 7644-7655Crossref PubMed Scopus (771) Google Scholar), apoptosis and cell survival (Rutkowski et al., 2006Rutkowski D.T. Arnold S.M. Miller C.N. Wu J. Li J. Gunnison K.M. Mori K. Sadighi Akha A.A. Raden D. Kaufman R.J. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins.PLoS Biol. 2006; 4: e374Crossref PubMed Scopus (616) Google Scholar), alternative splicing (Irimia et al., 2012Irimia M. Denuc A. Ferran J.L. Pernaute B. Puelles L. Roy S.W. Garcia-Fernàndez J. Marfany G. Evolutionarily conserved A-to-I editing increases protein stability of the alternative splicing factor Nova1.RNA Biol. 2012; 9: 12-21Crossref PubMed Scopus (26) Google Scholar), circadian rhythm (van Ooijen et al., 2011van Ooijen G. Dixon L.E. Troein C. Millar A.J. Proteasome function is required for biological timing throughout the twenty-four hour cycle.Curr. Biol. 2011; 21: 869-875Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), cell differentiation (Ramakrishna et al., 2011Ramakrishna S. Suresh B. Lim K.H. Cha B.H. Lee S.H. Kim K.S. Baek K.H. PEST motif sequence regulating human NANOG for proteasomal degradation.Stem Cells Dev. 2011; 20: 1511-1519Crossref PubMed Scopus (71) Google Scholar), development (Hirata et al., 2004Hirata H. Bessho Y. Kokubu H. Masamizu Y. Yamada S. Lewis J. Kageyama R. Instability of Hes7 protein is crucial for the somite segmentation clock.Nat. Genet. 2004; 36: 750-754Crossref PubMed Scopus (188) Google Scholar), and immunity (Babon et al., 2006Babon J.J. McManus E.J. Yao S. DeSouza D.P. Mielke L.A. Sprigg N.S. Willson T.A. Hilton D.J. Nicola N.A. Baca M. et al.The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability.Mol. Cell. 2006; 22: 205-216Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Altered protein half-life can lead to abnormal development and diseases such as cancer and neurodegeneration (Ciechanover, 2012Ciechanover A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting.Biochim. Biophys. Acta. 2012; 1824: 3-13Crossref PubMed Scopus (100) Google Scholar). For instance, artificially extending the half-life of the Hes7 transcription factor by ∼8 min severely disorganizes embryonic development in mice (Hirata et al., 2004Hirata H. Bessho Y. Kokubu H. Masamizu Y. Yamada S. Lewis J. Kageyama R. Instability of Hes7 protein is crucial for the somite segmentation clock.Nat. Genet. 2004; 36: 750-754Crossref PubMed Scopus (188) Google Scholar). Missense mutations in succinate dehydrogenase that increase turnover rates contribute to neuroendocrine tumors (Yang et al., 2012Yang C. Matro J.C. Huntoon K.M. Ye D.Y. Huynh T.T. Fliedner S.M. Breza J. Zhuang Z. Pacak K. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function.FASEB J. 2012; 26: 4506-4516Crossref PubMed Scopus (38) Google Scholar).The proteasome mediates controlled and selective degradation of most proteins in eukaryotic cells, and access to the proteasome is key to controlling the half-life of substrates (Goldberg, 2003Goldberg A.L. Protein degradation and protection against misfolded or damaged proteins.Nature. 2003; 426: 895-899Crossref PubMed Scopus (1648) Google Scholar, Hershko and Ciechanover, 1998Hershko A. Ciechanover A. The ubiquitin system.Annu. Rev. Biochem. 1998; 67: 425-479Crossref PubMed Scopus (6792) Google Scholar). Substrate recruitment to the proteasome is primarily mediated through their polyubiquitination by ubiquitin ligases (Komander and Rape, 2012Komander D. Rape M. The ubiquitin code.Annu. Rev. Biochem. 2012; 81: 203-229Crossref PubMed Scopus (2133) Google Scholar, Ravid and Hochstrasser, 2008Ravid T. Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system.Nat. Rev. Mol. Cell Biol. 2008; 9: 679-690Crossref PubMed Scopus (593) Google Scholar, Varshavsky, 2012Varshavsky A. The ubiquitin system, an immense realm.Annu. Rev. Biochem. 2012; 81: 167-176Crossref PubMed Scopus (213) Google Scholar). This mechanism regulates the half-life of proteins, which ranges from seconds to days (Belle et al., 2006Belle A. Tanay A. Bitincka L. Shamir R. O’Shea E.K. Quantification of protein half-lives in the budding yeast proteome.Proc. Natl. Acad. Sci. USA. 2006; 103: 13004-13009Crossref PubMed Scopus (519) Google Scholar, Kristensen et al., 2013Kristensen A.R. Gsponer J. Foster L.J. Protein synthesis rate is the predominant regulator of protein expression during differentiation.Mol. Syst. Biol. 2013; 9: 689Crossref PubMed Scopus (139) Google Scholar, Schwanhäusser et al., 2011Schwanhäusser B. Busse D. Li N. Dittmar G. Schuchhardt J. Wolf J. Chen W. Selbach M. Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (3941) Google Scholar). The large number of ubiquitin ligases and deubiquitinating enzymes encoded in eukaryotic genomes highlights the importance of this system (Hutchins et al., 2013Hutchins A.P. Liu S. Diez D. Miranda-Saavedra D. The repertoires of ubiquitinating and deubiquitinating enzymes in eukaryotic genomes.Mol. Biol. Evol. 2013; 30: 1172-1187Crossref PubMed Scopus (52) Google Scholar, Komander et al., 2009Komander D. Clague M.J. Urbé S. Breaking the chains: structure and function of the deubiquitinases.Nat. Rev. Mol. Cell Biol. 2009; 10: 550-563Crossref PubMed Scopus (1420) Google Scholar). Although the role of ubiquitination in delivering proteins to the proteasome is well established, it remains unclear to what extent intrinsic structural features of substrates influence their half-life once bound to the proteasome and whether such features have been exploited to alter half-life during evolution.An important feature implicated in affecting protein half-life is the presence of polypeptide regions that do not adopt a defined 3D structure, typically called intrinsically disordered, or unstructured regions (van der Lee et al., 2014van der Lee R. Buljan M. Lang B. Weatheritt R.J. Daughdrill G.W. Dunker A.K. Fuxreiter M. Gough J. Gsponer J. Jones D.T. et al.Classification of intrinsically disordered regions and proteins.Chem. Rev. 2014; 114: 6589-6631Crossref PubMed Scopus (1148) Google Scholar). Disordered regions are present in a large number of eukaryotic proteins and play key roles in protein function along with structured domains (Babu et al., 2012Babu M.M. Kriwacki R.W. Pappu R.V. Structural biology. Versatility from protein disorder.Science. 2012; 337: 1460-1461Crossref PubMed Scopus (157) Google Scholar). A number of genome-scale studies have investigated the relationship between the overall fraction of disordered residues of a protein and its half-life, but these have yielded contradictory results ranging from no correlation (Yen et al., 2008Yen H.C. Xu Q. Chou D.M. Zhao Z. Elledge S.J. Global protein stability profiling in mammalian cells.Science. 2008; 322: 918-923Crossref PubMed Scopus (319) Google Scholar) to weak correlation (Tompa et al., 2008Tompa P. Prilusky J. Silman I. Sussman J.L. Structural disorder serves as a weak signal for intracellular protein degradation.Proteins. 2008; 71: 903-909Crossref PubMed Scopus (90) Google Scholar) to a strong effect (Gsponer et al., 2008Gsponer J. Futschik M.E. Teichmann S.A. Babu M.M. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation.Science. 2008; 322: 1365-1368Crossref PubMed Scopus (348) Google Scholar). The reason for the inconsistencies is perhaps that these studies investigated correlations without the guidance provided by the biochemical mechanism by which disordered regions might contribute to protein turnover.In this work, we develop a theory of how disordered segments influence protein half-life, through a systematic analysis of multiple data sets describing sequence, structure, expression, evolutionary relationships, and experimental half-life measurements from both unicellular and multicellular organisms. We present evidence that proteins with a long terminal or internal disordered segment have a significantly shorter in vivo half-life in yeast on a genomic scale. The same relationship is found in mouse and human. Upon gene duplication, divergence in terminal and internal disordered segments leads to altered half-life of paralogous proteins. Many affected paralogs participate in signaling pathways, where altered half-life will influence signaling outcomes. We suggest specific biochemical mechanisms by which disordered segments may influence degradation rates, how these changes might modulate cellular function and phenotype, and how natural variation in the length and position of intrinsically disordered protein regions may contribute to the evolution of protein half-life.ResultsTo investigate the relationship between the structural architecture of proteins and their cellular stability, we inferred the disorder status of every residue in the proteomes of yeast, mouse, and human using the DISOPRED2 (Ward et al., 2004Ward J.J. Sodhi J.S. McGuffin L.J. Buxton B.F. Jones D.T. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life.J. Mol. Biol. 2004; 337: 635-645Crossref PubMed Scopus (1590) Google Scholar), IUPRED (Dosztányi et al., 2005Dosztányi Z. Csizmók V. Tompa P. Simon I. The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins.J. Mol. Biol. 2005; 347: 827-839Crossref PubMed Scopus (723) Google Scholar), and PONDR VLS1 (Obradovic et al., 2005Obradovic Z. Peng K. Vucetic S. Radivojac P. Dunker A.K. Exploiting heterogeneous sequence properties improves prediction of protein disorder.Proteins. 2005; 61: 176-182Crossref PubMed Scopus (430) Google Scholar) software. In vivo protein half-life data for yeast were obtained from a study that used strains in which proteins expressed from their endogenous promoter contained a tandem affinity purification (TAP) tag at the C terminus (Belle et al., 2006Belle A. Tanay A. Bitincka L. Shamir R. O’Shea E.K. Quantification of protein half-lives in the budding yeast proteome.Proc. Natl. Acad. Sci. USA. 2006; 103: 13004-13009Crossref PubMed Scopus (519) Google Scholar). After inhibition of protein synthesis, protein abundance was measured at three time points by western blotting with TAP antibodies. Protein turnover in mouse and human cells was measured using isotope labeling and mass spectrometry (Kristensen et al., 2013Kristensen A.R. Gsponer J. Foster L.J. Protein synthesis rate is the predominant regulator of protein expression during differentiation.Mol. Syst. Biol. 2013; 9: 689Crossref PubMed Scopus (139) Google Scholar, Schwanhäusser et al., 2011Schwanhäusser B. Busse D. Li N. Dittmar G. Schuchhardt J. Wolf J. Chen W. Selbach M. Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (3941) Google Scholar). We combined the information on protein half-life, and other large-scale data sets, with the position and length of disordered segments and analyzed the data using appropriate statistical tests (3,273 proteins in yeast, 4,502 in mouse, and 3,971 in human; Experimental Procedures; Table S1A; Figure S1A).Long N-Terminal Disordered Segments Contribute to Short Protein Half-Life In VivoWe first classified yeast proteins into two groups depending on the length of the disordered termini, treating the N and C termini separately: those with short (≤30 residues) and those with long (>30 residues) disordered tails (Figure 1A). The length cutoff was based on recent molecular models of the proteasome (da Fonseca et al., 2012da Fonseca P.C. He J. Morris E.P. Molecular model of the human 26S proteasome.Mol. Cell. 2012; 46: 54-66Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, Lander et al., 2012Lander G.C. Estrin E. Matyskiela M.E. Bashore C. Nogales E. Martin A. Complete subunit architecture of the proteasome regulatory particle.Nature. 2012; 482: 186-191Crossref PubMed Scopus (467) Google Scholar, Lasker et al., 2012Lasker K. Förster F. Bohn S. Walzthoeni T. Villa E. Unverdorben P. Beck F. Aebersold R. Sali A. Baumeister W. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach.Proc. Natl. Acad. Sci. USA. 2012; 109: 1380-1387Crossref PubMed Scopus (386) Google Scholar) and on in vitro biochemical studies using purified proteasomes showing that there is a critical minimum length of ∼30 residues that allows a disordered terminus of a ubiquitinated substrate to efficiently initiate degradation (Inobe et al., 2011Inobe T. Fishbain S. Prakash S. Matouschek A. Defining the geometry of the two-component proteasome degron.Nat. Chem. Biol. 2011; 7: 161-167Crossref PubMed Scopus (126) Google Scholar). Indeed, analysis of the yeast data confirms that protein half-life does not depend linearly on the length of disordered segments (Figure S1B; Supplemental Experimental Procedures).Proteins with a long disordered N terminus have a significantly shorter half-life compared to proteins with a short disordered N terminus (p = 5 × 10−6, Mann-Whitney U test, a nonparametric test for assessing whether two samples come from the same underlying distribution [H0]; Figure 1B). The approach for measuring half-lives in yeast involved C-terminal tagging with a TAP tag, which is 186 amino acids long and largely structured. Since all proteins had identical C termini due to the TAP tag, we should see little difference in half-life between proteins with long and short C-terminal disorder as characterized from the original genome sequence. Indeed, these groups display similar distributions of protein half-life (p = 0.99, Mann-Whitney U test; Figure 1C).In order to assess to what extent the disordered state of the N terminus affects half-life, we performed three analyses. First, we investigated proteins with a highly structured N terminus (>30 residues predicted to be structured) and found that they display a longer half-life compared to proteins with a long disordered N terminus (p = 2 × 10−7, Mann-Whitney U test; Figure 1D). Second, we classified the proteome into three groups of roughly equal size, based on their half-life: (1) short-lived proteins (half-life ≤ 30 min), (2) medium half-life proteins (31–70 min), and (3) long-lived proteins (>70 min) (Figure S1A). The distributions of the length of N-terminal disorder differ significantly across the three groups in a manner consistent with the above observations: proteins with a shorter half-life tend to have longer N-terminal disordered segments (p = 3 × 10−6, Kruskal-Wallis test, which extends the Mann-Whitney U test to three or more groups, Figures 1E and S1F). Again, this relationship is not true for the C terminus, because the TAP tag causes all proteins to have the same C terminus (p = 0.2, Kruskal-Wallis test; Figures S1E and S1F). Third, we quantified the effects of disordered segments on half-life by comparing conditional probabilities for finding proteins with and without long N-terminal disorder within specific half-life ranges. The likelihood of finding a protein with a short half-life among those that have long N-terminal disorder was two times higher than the “reverse” probability of finding proteins with long N-terminal disorder among those with short half-life (p[short half-life given long N-terminal disorder] = 0.44; p[long N-terminal disorder given short half-life] = 0.18; Tables 1A and S3A). This indicates that the presence of a long disordered N terminus often results in short half-life but proteins with short half-life need not always have a long N-terminal disordered segment. Thus, the presence of a disordered N terminus is linked to short half-life, but other properties also affect protein turnover (see Discussion).Table 1Conditional Probabilities for Intrinsically Disordered Segments and Protein Half-LifeView Large Image Figure ViewerDownload Hi-res image Download (PPT)See the top panel of this table and Figures 1 and 2 for a description of the definitions. See also Tables S3A (for part A) and S3B (for part B). Open table in a new tab Internal Disordered Segments Also Contribute to Short Protein Half-LifeThe proteasome not only digests proteins starting from their termini but also can cleave or initiate from disordered regions in the middle of the chain (Fishbain et al., 2011Fishbain S. Prakash S. Herrig A. Elsasser S. Matouschek A. Rad23 escapes degradation because it lacks a proteasome initiation region.Nat. Commun. 2011; 2: 192Crossref PubMed Scopus (71) Google Scholar, Liu et al., 2003Liu C.W. Corboy M.J. DeMartino G.N. Thomas P.J. Endoproteolytic activity of the proteasome.Science. 2003; 299: 408-411Crossref PubMed Scopus (345) Google Scholar, Piwko and Jentsch, 2006Piwko W. Jentsch S. Proteasome-mediated protein processing by bidirectional degradation initiated from an internal site.Nat. Struct. Mol. Biol. 2006; 13: 691-697Crossref PubMed Scopus (83) Google Scholar, Prakash et al., 2004Prakash S. Tian L. Ratliff K.S. Lehotzky R.E. Matouschek A. An unstructured initiation site is required for efficient proteasome-mediated degradation.Nat. Struct. Mol. Biol. 2004; 11: 830-837Crossref PubMed Scopus (355) Google Scholar, Takeuchi et al., 2007Takeuchi J. Chen H. Coffino P. Proteasome substrate degradation requires association plus extended peptide.EMBO J. 2007; 26: 123-131Crossref PubMed Scopus (102) Google Scholar, Zhao et al., 2010Zhao M. Zhang N.Y. Zurawel A. Hansen K.C. Liu C.W. Degradation of some polyubiquitinated proteins requires an intrinsic proteasomal binding element in the substrates.J. Biol. Chem. 2010; 285: 4771-4780Crossref PubMed Scopus (27) Google Scholar). The catalytic residues for proteolysis are buried deep within the proteasome core particle, accessible only through a long narrow channel, and the same is true for the ATPase motor that drives protein substrates through the degradation channel (da Fonseca et al., 2012da Fonseca P.C. He J. Morris E.P. Molecular model of the human 26S proteasome.Mol. Cell. 2012; 46: 54-66Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, Lander et al., 2012Lander G.C. Estrin E. Matyskiela M.E. Bashore C. Nogales E. Martin A. Complete subunit architecture of the proteasome regulatory particle.Nature. 2012; 482: 186-191Crossref PubMed Scopus (467) Google Scholar, Lasker et al., 2012Lasker K. Förster F. Bohn S. Walzthoeni T. Villa E. Unverdorben P. Beck F. Aebersold R. Sali A. Baumeister W. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach.Proc. Natl. Acad. Sci. USA. 2012; 109: 1380-1387Crossref PubMed Scopus (386) Google Scholar). To reach these sites, a disordered segment in the middle of a protein has to be longer than a segment at a protein terminus (Fishbain et al., 2011Fishbain S. Prakash S. Herrig A. Elsasser S. Matouschek A. Rad23 escapes degradation because it lacks a proteasome initiation region.Nat. Commun. 2011; 2: 192Crossref PubMed Scopus (71) Google Scholar). Therefore, to investigate whether the presence of internal disorder influences protein half-life, we identified proteasome-susceptible internal disordered segments as continuous stretches of at least 40 disordered amino acids (see Discussion). Proteins that contain such an internal disordered segment have a significantly shorter half-life than proteins that do not (p = 3 × 10−29, Mann-Whitney U test; Figure 2A). This observation is robust to our choice of cutoff used for detecting internal disordered segments, but systematically varying the length cutoff revealed that maximal difference in median half-life is obtained for a value of 40 amino acids (Table S1E). Further, the relationship is independent of N-terminal disorder, as the half-life of proteins with internal disordered segments is significantly lower than of those without, regardless of the length of the disordered terminus (Figure 2B).Figure 2The Effects of Internal Disordered Segments on Protein Half-LifeShow full caption(A) Boxplots of protein half-life distributions for different groups of yeast proteins that contain (dark red) or lack (light red) an internal disordered segment (defined as a continuous stretch of ≥40 disordered residues), subclassified based on (B and D) the length of N-terminal disorder (as in Figure 1: long, >30 residues or short, ≤ 30 residues) and (C) the number of internal disordered segments (from zero, top, to three or more, bottom). Each protein is present in only one category per panel. See Figure 1 for further information. See also Figures S2 and S3 and Tables S1 and S4.View Large Image Figure ViewerDownload Hi-res image Download (PPT)To quantify the contribution of internal disorder to protein half-life, we computed conditional probabilities for finding proteins with and without internal disordered segments within specific half-life ranges. The probability of observing a protein with a short half-life among those that contain an internal disordered segment is high and comparable to the “reverse” probability of finding a protein containing an internal disordered segment among those with short half-life (p[short half-life given internal disordered segment] = 0.45; p[internal disordered segment given short half-life] = 0.49; Tables 1B and S3B). This suggests that presence or absence of an internal disordered segment is an important determinant of the half-life of a protein.Terminal and Internal Disordered Segments Have Combined Effects on Half-LifeInterestingly, proteins with multiple internal disordered segments have even shorter half-lives than proteins with a single segment (Figures 2C and S2C). This prompted us to investigate the combinatorial effects of terminal and internal disordered segments. Indeed, proteins that have both a long terminal disordered segment and an internal disordered segment tend to have the shortest half-lives (Figure 2D). Furthermore, the probability of having either a terminal or an internal disordered segment given that a protein has a short half-life is the highest (p[long N-terminal or internal disorder given short half-life] = 0.57; Table 1C). Consistent with this observation, we find that the probability of having both terminal and internal disordered segments among proteins with a long half-life is very low (p[long N-terminal and internal disorder given long half-life] = 0.04; Table 1C). Taken together, these results suggest that disordered segments are modular in their ability to affect protein half-life and that these segments can act in a combinatorial manner to accentuate their effects.The Effects of Disordered Segments on Half-Life Are Independent of the Overall Disorder DegreeSo far, we have investigated the effects of continuous stretches of disordered residues (i.e., disordered segments) on protein turnover. However, the fraction of disordered residues (i.e., overall degree of disorder), which is an estimate of the packing, folding, and structural stability of a protein, also correlates with half-life, although previous studies disagree on the extent of the effect (Gsponer et al., 2008Gsponer J. Futschik M.E. Teichmann S.A. Babu M.M. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation.Science. 2008; 322: 1365-1368Crossref PubMed Scopus (348) Google Scholar, Tompa et al., 2008Tompa P. Prilusky J. Silman I. Sussman J.L. Structural disorder serves as a weak signal for intracellular protein degradation.Proteins. 2008; 71: 903-909Crossref PubMed Scopus (90) Google Scholar, Yen et al., 2008Yen H.C. Xu Q. Chou D.M. Zhao Z. Elledge S.J. Global protein stability profiling in mammalian cells.Science. 2008; 322: 918-923Crossref PubMed Scopus (319) Google Scholar). Proteins with a greater overall disorder degree generally contain longer terminal and internal disordered segments (Figure S3A). To determine whether the effects of disordered segments on protein turnover (Figures 1 and 2) are independent of the overall degree of disorder, we matched proteins that have a similar fraction of disordered residues but have varying combinations of disordered segments (long or short N-terminal disorder and/or presence or absence of internal disordered segments; Supplemental Results; Figure S3B).Comparison of the half-life distributions of proteins from different classes with similar overall disorder degrees (Figure S3C) reveals similar trends as the analysis that uses all proteins (Figure 2D): proteins with both long N-terminal and internal disordered segments typically have the shortest half-lives, followed by proteins with either long internal or long N-terminal disordered segments. Proteins without disordered segments typically have the longest half-lives. The effect sizes of the differences between the half-life distributions are comparable when using all or only proteins with matched overall disorder degree (Figure S3D, upper triangles). Furthermore, most half-life distributions are significantly different, though p values are less significant due to smaller sample sizes (Figure S3D, lower triangles). These results indicate that long disordered segments at the N terminus or internally are important intrinsic features that contribute to shorter protein half-life in living cells and that these effects are independent of the fraction of disordered residues across the whole protein. It should, however, be noted that this does not rule out an additional effect of the overall disorder degree on half-life, i.e., among proteins that do or do not have a disordered segment, proteins with higher degrees of overall disorder tend to have a lower half-life compared to those with a lower degree of disorder (see Discussion).Disordered Segments Have Direct Effects on Half-Life Rather than Acting Indirectly by Embedding Destruction SignalsDisordered segments could influence half-life either indirectly, by embedding short peptide motifs that serve as destruction signals such as ubiquitination sites or docking sites for ubiquitinating enzymes (Ravid and Hochstrasser, 2008Ravid T. Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system.Nat. Rev. Mol. Cell Biol. 2008; 9: 679-" @default.
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• W2159457776 title "Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution" @default.
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• W2159457776 doi "https://doi.org/10.1016/j.celrep.2014.07.055" @default.
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