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Early folding events protect aggregation-prone regions of a ?-rich protein.

ABSTRACT: Protein folding and aggregation inevitably compete with one another. This competition is even keener for proteins with frustrated landscapes, such as those rich in ? structure. It is interesting that, despite their rugged energy landscapes and high ? sheet content, intracellular lipid-binding proteins (iLBPs) appear to successfully avoid aggregation, as they are not implicated in aggregation diseases. In this study, we used a canonical iLBP, cellular retinoic acid-binding protein 1 (CRABP1), to understand better how folding is favored over aggregation. Analysis of folding kinetics of point mutants reveals that the folding pathway of CRABP1 involves early barrel closure. This folding mechanism protects sequences in CRABP1 that comprise cores of aggregates as identified by nuclear magnetic resonance. The amino acid conservation pattern in other iLBPs suggests that early barrel closure may be a general strategy for successful folding and minimization of aggregation. We suggest that folding mechanisms in general may incorporate steps that disfavor aggregation.

SUBMITTER: Budyak IL

PROVIDER: S-EPMC3630246 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Early folding events protect aggregation-prone regions of a β-rich protein.

Budyak Ivan L IL Krishnan Beena B Marcelino-Cruz Anna M AM Ferrolino Mylene C MC Zhuravleva Anastasia A Gierasch Lila M LM

Structure (London, England : 1993) 20130301 3

Protein folding and aggregation inevitably compete with one another. This competition is even keener for proteins with frustrated landscapes, such as those rich in β structure. It is interesting that, despite their rugged energy landscapes and high β sheet content, intracellular lipid-binding proteins (iLBPs) appear to successfully avoid aggregation, as they are not implicated in aggregation diseases. In this study, we used a canonical iLBP, cellular retinoic acid-binding protein 1 (CRABP1), to ...[more]

PMID: 23454187

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Project description:The various roles that aggregation prone regions (APRs) are capable of playing in proteins are investigated here via comprehensive analyses of multiple non-redundant datasets containing randomly generated amino acid sequences, monomeric proteins, intrinsically disordered proteins (IDPs) and catalytic residues. Results from this study indicate that the aggregation propensities of monomeric protein sequences have been minimized compared to random sequences with uniform and natural amino acid compositions, as observed by a lower average aggregation propensity and fewer APRs that are shorter in length and more often punctuated by gate-keeper residues. However, evidence for evolutionary selective pressure to disrupt these sequence regions among homologous proteins is inconsistent. APRs are less conserved than average sequence identity among closely related homologues (?80% sequence identity with a parent) but APRs are more conserved than average sequence identity among homologues that have at least 50% sequence identity with a parent. Structural analyses of APRs indicate that APRs are three times more likely to contain ordered versus disordered residues and that APRs frequently contribute more towards stabilizing proteins than equal length segments from the same protein. Catalytic residues and APRs were also found to be in structural contact significantly more often than expected by random chance. Our findings suggest that proteins have evolved by optimizing their risk of aggregation for cellular environments by both minimizing aggregation prone regions and by conserving those that are important for folding and function. In many cases, these sequence optimizations are insufficient to develop recombinant proteins into commercial products. Rational design strategies aimed at improving protein solubility for biotechnological purposes should carefully evaluate the contributions made by candidate APRs, targeted for disruption, towards protein structure and activity.

Dataset Information

Early folding events protect aggregation-prone regions of a ?-rich protein.

Publications

Early folding events protect aggregation-prone regions of a β-rich protein.

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