The Evolution of Transmembrane Helix Kinks and the Structural Diversity of G Protein-Coupled Receptors

One of the hallmarks of membrane protein structure is the high frequency of transmembrane helix kinks, which commonly occur at proline residues. Because the proline side chain usually precludes normal helix geometry, it is reasonable to expect that proline residues generate these kinks. We observe,...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 4; pp. 959 - 963
Main Authors Yohannan, Sarah, Faham, Salem, Yang, Duan, Whitelegge, Julian P., Bowie, James U.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 27.01.2004
National Acad Sciences
Subjects
Bacteriorhodopsins
Biochemistry
Biological Sciences
Biophysics
Evolution
Free energy
GTP-Binding Proteins - metabolism
Hydrogen bonds
Lead
Membrane proteins
Membranes
Models, Molecular
Molecular structure
Mutation
Protein Conformation
Proteins
Receptors
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - metabolism
Sequence alignment
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Summary:One of the hallmarks of membrane protein structure is the high frequency of transmembrane helix kinks, which commonly occur at proline residues. Because the proline side chain usually precludes normal helix geometry, it is reasonable to expect that proline residues generate these kinks. We observe, however, that the three prolines in bacteriorhodopsin transmembrane helices can be changed to alanine with little structural consequences. This finding leads to a conundrum: if proline is not required for helix bending, why are prolines commonly present at bends in transmembrane helices? We propose an evolutionary hypothesis in which a mutation to proline initially induces the kink. The resulting packing defects are later repaired by further mutation, thereby locking the kink in the structure. Thus, most prolines in extant proteins can be removed without major structural consequences. We further propose that nonproline kinks are places where vestigial prolines were later removed during evolution. Consistent with this hypothesis, at 14 of 17 nonproline kinks in membrane proteins of known structure, we find prolines in homologous sequences. Our analysis allows us to predict kink positions with >90% reliability. Kink prediction indicates that different G protein-coupled receptor proteins have different kink patterns and therefore different structures.
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This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: bR, bacteriorhodopsin; GPCR, G protein-coupled receptor; PRC, photosynthetic reaction center; COX, cytochrome C oxidase; MGR8, metabotropic glutamate receptor 8.
To whom correspondence should be addressed. E-mail: bowie@mbi.ucla.edu.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 1Q5J and 1Q5I).
Edited by Douglas C. Rees, California Institute of Technology, Pasadena, CA, and approved November 25, 2003
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0306077101