A pH-Mediated Topological Switch within the N-Terminal Domain of Human Caveolin-3

作者：Kim Ji Hun; Schlebach Jonathan P; Lu Zhenwei; Peng Dungeng; Reasoner Kaitlyn C; Sanders Charles R^*

来源：Biophysical Journal, 2016, 110(11): 2475-2485.

DOI：10.1016/j.bpj.2016.05.004

Caveolins mediate the formation of caveolae, which are small omega-shaped membrane invaginations involved in a variety of cellular processes. There are three caveolin isoforms, the third of which (Cav3) is expressed in smooth and skeletal muscles. Mutations in Cav3 cause a variety of human muscular diseases. In this work, we characterize the secondary structure, dynamics, and topology of the monomeric form of the full-length lipidated protein. Cav3 consists of a series of membrane- embedded or surface-associated helical elements connected by extramembrane connecting loops or disordered domains. Our results also reveal that the N-terminal domain undergoes a large scale pH-mediated topological rearrangement between soluble and membrane-anchored forms. Considering that roughly one-third of pathogenic mutations in Cav3 influence charged residues located in this domain, we hypothesize that this transition is likely to be relevant to the molecular basis of Cav3-linked diseases. These results provide insight into the structure of Cav3 and set the stage for mechanistic investigations of the effects of pathogenic mutations.

• 出版日期2016-6-7