A pH-Mediated Topological Switch within the N-Terminal Domain of Human Caveolin-3.
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.
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Biotechnology, Research Institute (RIBHS) and College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Korea.
Ji-Hun
JH
Kim
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Jonathan P
JP
Schlebach
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Zhenwei
Z
Lu
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Dungeng
D
Peng
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Kaitlyn C
KC
Reasoner
Departments of Biochemistry and Medicine and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: chuck.sanders@vanderbilt.edu.
Charles R
CR
Sanders
D000595:Amino Acid Sequence; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008567:Membranes, Artificial; D008823:Micelles; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010715:Phosphatidylglycerols / Q000737:chemistry; D017433:Protein Structure, Secondary; D012995:Solubility; D012996:Solutions
C417736:CAV3 protein, human; D051244:Caveolin 3; D008567:Membranes, Artificial; D008823:Micelles; D010715:Phosphatidylglycerols; D012996:Solutions; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol