title: BiP clustering facilitates protein folding in the endoplasmic reticulum.
abstract: The chaperone BiP participates in several regulatory processes within the endoplasmic reticulum (ER): translocation, protein folding, and ER-associated degradation. To facilitate protein folding, a cooperative mechanism known as entropic pulling has been proposed to demonstrate the molecular-level understanding of how multiple BiP molecules bind to nascent and unfolded proteins. Recently, experimental evidence revealed the spatial heterogeneity of BiP within the nuclear and peripheral ER of S. cerevisiae (commonly referred to as 'clusters'). Here, we developed a model to evaluate the potential advantages of accounting for multiple BiP molecules binding to peptides, while proposing that BiP's spatial heterogeneity may enhance protein folding and maturation. Scenarios were simulated to gauge the effectiveness of binding multiple chaperone molecules to peptides. Using two metrics: folding efficiency and chaperone cost, we determined that the single binding site model achieves a higher efficiency than models characterized by multiple binding sites, in the absence of cooperativity. Due to entropic pulling, however, multiple chaperones perform in concert to facilitate the resolubilization and ultimate yield of folded proteins. As a result of cooperativity, multiple binding site models used fewer BiP molecules and maintained a higher folding efficiency than the single binding site model. These insilico investigations reveal that clusters of BiP molecules bound to unfolded proteins may enhance folding efficiency through cooperative action via entropic pulling.
authors.affiliation: Department of Applied Mathematics, University of California, Merced, Merced, California, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Griesemer
authors.affiliation: Department of Chemical Engineering, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Carissa
authors.initials: C
authors.lastname: Young
authors.affiliation: Department of Chemical Engineering, University of Delaware, Newark, Delaware, United States of America; Department of Chemical and Biomolecular Engineering, Tulane University, New Orleans, Louisiana, United States of America.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Robinson
authors.affiliation: Department of Computer Science, University of California, Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Petzold
mesh_terms: D019295:Computational Biology; D004721:Endoplasmic Reticulum / Q000737:chemistry* / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins