title: A feature analysis of lower solubility proteins in three eukaryotic systems.
abstract: Because misfolded and damaged proteins can form potentially harmful aggregates, all living organisms have evolved a wide variety of quality control mechanisms. However, the timely clearance of aggregation-prone species may not always be achieved, potentially leading to the accumulation of low solubility proteins. At the same time, promiscuity, which can be a driving force for aggregation, is also important to the functionality of certain proteins which have a large number of interaction partners. Considerable efforts have been made towards characterizing why some proteins appear to be more aggregation-prone than others. In this study, we analyze the features of proteins which precipitate following centrifugation in unstressed yeast cells, human SH-SY5Y cells and mouse brain tissue. By normalizing for protein abundance, we devised an approach whereby lower solubility proteins are reliably identified. Our findings indicate that these tend to be longer, low abundance proteins, which contain fewer hydrophobic amino acids. Furthermore, low solubility proteins also contain more low complexity and disordered regions. Overall, we observed an increase in features that link low solubility proteins to functional aggregates. Our results indicate that lower solubility proteins from three biologically distinct model systems share several common traits, shedding light on potentially universal solubility determinants.
  
  
  CONCLUSIONS
  We set up a novel approach to identify lower solubility proteins in unstressed cells by comparing precipitated proteins with those that remain soluble after centrifugation. By analyzing three eukaryotic model systems in parallel, we were able to identify traits which cross the species barrier, as well as species-specific characteristics. Notably, our analyses revealed a number of primary and secondary structural features that set apart lower solubility proteins, a number of which connected them to a greater potential for promiscuity. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras.
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada.
authors.forename: Razvan F
authors.initials: RF
authors.lastname: Albu
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada.
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Chan
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada.
authors.forename: Mang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada.
authors.forename: Eric T C
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Taghizadeh
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
authors.forename: Arya E
authors.initials: AE
authors.lastname: Mehran
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada.
authors.forename: Jörg
authors.initials: J
authors.lastname: Gsponer
authors.affiliation: Department of Biochemistry and Molecular Biology and Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, V6T 1Z4 Canada. Electronic address: mayor@mail.ubc.ca.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mayor
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D066329:Protein Aggregates; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
chemical_list: D066329:Protein Aggregates; D011994:Recombinant Proteins
keywords: Computational biology; Functional aggregation; Low solubility proteins; Mass spectrometry; Proteomics; Proteostasis