Linked Life Data

12871954

Source:http://linkedlifedata.com/resource/pubmed/id/12871954

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
40
pubmed:dateCreated
2003-9-29
pubmed:abstractText
L125R, a severe retinitis pigmentosa rhodopsin missense mutation, results in rhodopsin protein misfolding, retinal degeneration, and ultimately blindness. The initiating structural events leading to this protein misfolding are unknown. Through the use of compensatory mutations, in conjunction with crystal structure-based molecular analysis, we established that the larger and positively charged Arg replacing Leu125 sterically hinders both the adjacent Trp126 and a critical interhelical interaction between transmembrane III (TM III) and transmembrane V (TM V; Glu122 and His211 salt bridge). Further, analysis of another retinitis pigmentosa mutation, A164V (TM IV), indicates that the larger Val interferes with residues Leu119 and Ile123 on TM III, leading to the disruption of the same critical Glu122-His211 salt bridge (TM III-TM V interaction). Combined, these localized defects in interhelical interactions cause structural changes that interfere with the ability of opsin to bind 11-cis-retinal. These distortions ultimately lead to the formation of an abnormal disulfide bond, severe protein instability, aggregation, and endoplasmic reticulum retention. In the absence of a crystal or NMR structure of each retinitis pigmentosa mutation, compensatory mutagenesis and crystal structure-based analysis are powerful tools in determining the localized molecular disturbances. A detailed understanding of the initiating local perturbations created by missense mutations such as these, not only identifies critical factors required for correct folding and stability, but additionally opens avenues for rational drug design, mimicking the compensatory mutations and stabilizing the protein.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
3
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
39020-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12871954-Amino Acid Sequence, pubmed-meshheading:12871954-Animals, pubmed-meshheading:12871954-Blotting, Western, pubmed-meshheading:12871954-COS Cells, pubmed-meshheading:12871954-Cell Membrane, pubmed-meshheading:12871954-Disulfides, pubmed-meshheading:12871954-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:12871954-Humans, pubmed-meshheading:12871954-Leucine, pubmed-meshheading:12871954-Microscopy, Fluorescence, pubmed-meshheading:12871954-Models, Molecular, pubmed-meshheading:12871954-Molecular Sequence Data, pubmed-meshheading:12871954-Mutation, pubmed-meshheading:12871954-Mutation, Missense, pubmed-meshheading:12871954-Protein Binding, pubmed-meshheading:12871954-Protein Conformation, pubmed-meshheading:12871954-Protein Folding, pubmed-meshheading:12871954-Protein Structure, Secondary, pubmed-meshheading:12871954-Retinitis Pigmentosa, pubmed-meshheading:12871954-Rhodopsin, pubmed-meshheading:12871954-Software, pubmed-meshheading:12871954-Spectrophotometry, pubmed-meshheading:12871954-Temperature, pubmed-meshheading:12871954-Time Factors, pubmed-meshheading:12871954-Transfection, pubmed-meshheading:12871954-Tryptophan, pubmed-meshheading:12871954-Ultraviolet Rays
pubmed:year
2003
pubmed:articleTitle
Retinitis pigmentosa rhodopsin mutations L125R and A164V perturb critical interhelical interactions: new insights through compensatory mutations and crystal structure analysis.
pubmed:affiliation
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't