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- W2074455942 abstract "It is now widely recognized that intrinsically unstructured (or disordered) proteins (IUPs or IDPs) are found in organisms from all kingdoms of life. In eukaryotes, IUPs are highly abundant and perform a wide range of biological functions, including regulation and signaling. Despite an increased level of interest in understanding the structural biology of IUPs and IDPs, questions regarding the mechanisms through which disordered proteins perform their biological function(s) remain. In other words, what are the relationships between disorder and function for IUPs? There are several excellent reviews that discuss the structural properties of IUPs and IDPs since 2005 [Receveur-Brechot, V., et al. (2006) Proteins 62, 24-45; Mittag, T., and Forman-Kay, J. D. (2007) Curr. Opin. Struct. Biol. 17, 3-14; Dyson, H. J., and Wright, P. E. (2005) Nat. Rev. Mol. Cell Biol. 6, 197-208]. Here, we briefly review general concepts pertaining to IUPs and then discuss our structural, biophysical, and biochemical studies of two IUPs, p21 and p27, which regulate the mammalian cell division cycle by inhibiting cyclin-dependent kinases (Cdks). Some segments of these two proteins are partially folded in isolation, and they fold further upon binding their biological targets. Interestingly, some portions of p27 remain flexible after binding to and inhibiting the Cdk2-cyclin A complex. This residual flexibility allows otherwise buried tyrosine residues within p27 to be phosphorylated by non-receptor tyrosine kinases (NRTKs). Tyrosine phosphorylation relieves kinase inhibition, triggering Cdk2-mediated phosphorylation of a threonine residue within the flexible C-terminus of p27. This, in turn, marks p27 for ubiquitination and proteasomal degradation, unleashing full Cdk2 activity which drives cell cycle progression. p27, thus, constitutes a conduit for transmission of proliferative signals via post-translational modifications. The term conduit is used here to connote a means of transmission of molecular signals which, in the case of p27, correspond to tyrosine and threonine phosphorylation, ubiquitination, and, ultimately, proteolytic degradation. Transmission of these multiple signals is enabled by the inherent flexibility of p27 which persists even after tight binding to the Cdk2-cyclin A complex. Importantly, activation of the p27 signaling conduit by oncogenic NRTKs contributes to tumorigenesis in some human cancers, including chronic myelogenous leukemia (CML) [Grimmler, M., et al. (2007) Cell 128, 269-280] and breast cancer [Chu, I., et al. (2007) Cell 128, 281-294]. Other IUPs may participate in conceptually similar molecular signaling conduits, and dysregulation of these putative conduits may contribute to other human diseases. Detailed study of these IUPs, both alone and within functional complexes, is required to test these hypotheses and to more fully understand the relationships between protein disorder and biological function." @default.
- W2074455942 created "2016-06-24" @default.
- W2074455942 creator A5001475306 @default.
- W2074455942 creator A5015019969 @default.
- W2074455942 creator A5017667786 @default.
- W2074455942 creator A5075327741 @default.
- W2074455942 date "2008-07-01" @default.
- W2074455942 modified "2023-10-10" @default.
- W2074455942 title "Regulation of Cell Division by Intrinsically Unstructured Proteins: Intrinsic Flexibility, Modularity, and Signaling Conduits" @default.
- W2074455942 cites W1520645352 @default.
- W2074455942 cites W1540559701 @default.
- W2074455942 cites W1965127482 @default.
- W2074455942 cites W1966528069 @default.
- W2074455942 cites W1967203779 @default.
- W2074455942 cites W1967974247 @default.
- W2074455942 cites W1968415569 @default.
- W2074455942 cites W1972497797 @default.
- W2074455942 cites W1974959278 @default.
- W2074455942 cites W1975121208 @default.
- W2074455942 cites W1976873804 @default.
- W2074455942 cites W1980015132 @default.
- W2074455942 cites W1988565419 @default.
- W2074455942 cites W1990659194 @default.
- W2074455942 cites W1990743609 @default.
- W2074455942 cites W1992285513 @default.
- W2074455942 cites W1993170641 @default.
- W2074455942 cites W1993294667 @default.
- W2074455942 cites W1994151152 @default.
- W2074455942 cites W1995009821 @default.
- W2074455942 cites W1996413533 @default.
- W2074455942 cites W1996588976 @default.
- W2074455942 cites W2000879731 @default.
- W2074455942 cites W2003022823 @default.
- W2074455942 cites W2003282728 @default.
- W2074455942 cites W2003561135 @default.
- W2074455942 cites W2004565169 @default.
- W2074455942 cites W2006192061 @default.
- W2074455942 cites W2006199861 @default.
- W2074455942 cites W2008789097 @default.
- W2074455942 cites W2009564452 @default.
- W2074455942 cites W2010912571 @default.
- W2074455942 cites W2011983814 @default.
- W2074455942 cites W2013491063 @default.
- W2074455942 cites W2013593586 @default.
- W2074455942 cites W2016170088 @default.
- W2074455942 cites W2019057425 @default.
- W2074455942 cites W2023487073 @default.
- W2074455942 cites W2026004604 @default.
- W2074455942 cites W2030776726 @default.
- W2074455942 cites W2032911291 @default.
- W2074455942 cites W2033782813 @default.
- W2074455942 cites W2034299708 @default.
- W2074455942 cites W2034942377 @default.
- W2074455942 cites W2039037322 @default.
- W2074455942 cites W2040323778 @default.
- W2074455942 cites W2040412126 @default.
- W2074455942 cites W2041822226 @default.
- W2074455942 cites W2043383780 @default.
- W2074455942 cites W2043591644 @default.
- W2074455942 cites W2049283940 @default.
- W2074455942 cites W2049476357 @default.
- W2074455942 cites W2049477140 @default.
- W2074455942 cites W2051405565 @default.
- W2074455942 cites W2055085859 @default.
- W2074455942 cites W2058454436 @default.
- W2074455942 cites W2060328944 @default.
- W2074455942 cites W2068997227 @default.
- W2074455942 cites W2069494008 @default.
- W2074455942 cites W2073745520 @default.
- W2074455942 cites W2077116876 @default.
- W2074455942 cites W2080004661 @default.
- W2074455942 cites W2085593164 @default.
- W2074455942 cites W2086756954 @default.
- W2074455942 cites W2087395511 @default.
- W2074455942 cites W2092683495 @default.
- W2074455942 cites W2094600324 @default.
- W2074455942 cites W2099452199 @default.
- W2074455942 cites W2102322227 @default.
- W2074455942 cites W2104437738 @default.
- W2074455942 cites W2110790611 @default.
- W2074455942 cites W2114823344 @default.
- W2074455942 cites W2115726565 @default.
- W2074455942 cites W2117017117 @default.
- W2074455942 cites W2119693327 @default.
- W2074455942 cites W2120881407 @default.
- W2074455942 cites W2121619780 @default.
- W2074455942 cites W2121802410 @default.
- W2074455942 cites W2122558314 @default.
- W2074455942 cites W2126303237 @default.
- W2074455942 cites W2128142027 @default.
- W2074455942 cites W2128705810 @default.
- W2074455942 cites W2131965976 @default.
- W2074455942 cites W2137530206 @default.
- W2074455942 cites W2140616882 @default.
- W2074455942 cites W2141027008 @default.
- W2074455942 cites W2149472608 @default.
- W2074455942 cites W2152107294 @default.
- W2074455942 cites W2153451248 @default.