title: Intrinsically disordered segments affect protein half-life in the cell and during evolution.
abstract: 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.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands. Electronic address: rvdlee@mrc-lmb.cam.ac.uk.
authors.forename: Robin
authors.initials: R
authors.lastname: van der Lee
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lang
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Kai
authors.initials: K
authors.lastname: Kruse
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, East Mall, Vancouver BC V6T 1Z4, Canada.
authors.forename: Jörg
authors.initials: J
authors.lastname: Gsponer
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sánchez de Groot
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.affiliation: Department of Molecular Biosciences and Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Matouschek
authors.affiliation: MTA-DE Momentum Laboratory of Protein Dynamics, Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Monika
authors.initials: M
authors.lastname: Fuxreiter
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: madanm@mrc-lmb.cam.ac.uk.
authors.forename: M Madan
authors.initials: MM
authors.lastname: Babu
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D006207:Half-Life; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D012984:Software
chemical_list: D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins