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How ?-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.

ABSTRACT: Lipids are produced site-specifically in cells and then distributed nonrandomly among membranes via vesicular and nonvesicular trafficking mechanisms. The latter involves soluble amphitropic proteins extracting specific lipids from source membranes to function as molecular solubilizers that envelope their insoluble cargo before transporting it to destination sites. Lipid-binding and lipid transfer structural motifs range from multi-?-strand barrels, to ?-sheet cups and baskets covered by ?-helical lids, to multi-?-helical bundles and layers. Here, we focus on how ?-helical proteins use amphipathic helical layering and bundling to form modular lipid-binding compartments and discuss the functional consequences. Preformed compartments generally rely on intramolecular disulfide bridging to maintain conformation (e.g., albumins, nonspecific lipid transfer proteins, saposins, nematode polyprotein allergens/antigens). Insights into nonpreformed hydrophobic compartments that expand and adapt to accommodate a lipid occupant are few and provided mostly by the three-layer, ?-helical ligand-binding domain of nuclear receptors. The simple but elegant and nearly ubiquitous two-layer, ?-helical glycolipid transfer protein (GLTP)-fold now further advances understanding.

SUBMITTER: Malinina L

PROVIDER: S-EPMC7935428 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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How α-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.

Malinina Lucy L Patel Dinshaw J DJ Brown Rhoderick E RE

Annual review of biochemistry 20170330

Lipids are produced site-specifically in cells and then distributed nonrandomly among membranes via vesicular and nonvesicular trafficking mechanisms. The latter involves soluble amphitropic proteins extracting specific lipids from source membranes to function as molecular solubilizers that envelope their insoluble cargo before transporting it to destination sites. Lipid-binding and lipid transfer structural motifs range from multi-β-strand barrels, to β-sheet cups and baskets covered by α-helic ...[more]

PMID: 28375742

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Project description:Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes and preform critical roles in many cellular processes, most often through the association with globular proteins. Despite lacking a stable three-dimensional structure by themselves, they may acquire a defined conformation upon binding globular targets. The most common type of secondary structure acquired by these binding motifs entails formation of an α-helix. It has been hypothesized that such disorder-to-order transitions are associated with a significant free energy penalty due to IDP folding, which reduces the overall IDP-target affinity. However, the exact magnitude of IDP folding penalty in α-helical binding motifs has not been systematically estimated. Here, we report the folding penalty contributions for 30 IDPs undergoing folding-upon-binding and find that the average IDP folding penalty is +2.0 kcal/mol and ranges from 0.7 to 3.5 kcal/mol. We observe that the folding penalty scales approximately linearly with the change in IDP helicity upon binding, which provides a simple empirical way to estimate folding penalty. We analyze to what extent do pre-structuring and target-bound IDP dynamics (fuzziness) reduce the folding penalty and find that these effects combined, on average, reduce the folding cost by around half. Taken together, the presented analysis provides a quantitative basis for understanding the role of folding penalty in IDP-target interactions and introduces a method estimate this quantity. Estimation and reduction of IDP folding penalty may prove useful in the rational design of helix-stabilized inhibitors of IDP-target interactions. STATEMENT: The α-helical binding motifs are ubiquitous among the intrinsically disordered proteins (IDPs). Upon binding their targets, they undergo a disorder-to-order transition, which is accompanied by a significant folding penalty whose magnitude is generally not known. Here, we use recently developed statistical-thermodynamic model to estimate the folding penalties for 30 IDPs and clarify the roles of IDP pre-folding and bound-state dynamics in reducing the folding penalty.

Dataset Information

How ?-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.

Publications

How α-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.

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