Linked Life Data

2694933

Source:http://linkedlifedata.com/resource/pubmed/id/2694933

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
1990-3-13
pubmed:abstractText
There is tremendous variability in the importance of individual amino acids in protein sequences. On the one hand, nonconservative residue substitutions can be tolerated with no loss of activity at many residue positions, especially those exposed on the protein surface. On the other hand, destabilizing mutations can occur at a large number of different sites in a protein, and for many proteins such mutations account for more than half of the randomly isolated missense mutations that confer a defective phenotype. At sites that are key determinants of stability or activity, even residue substitutions that are generally considered to be conservative (e.g., Glu in equilibrium Asp, Asn in equilibrium Asp, Ile in equilibrium Leu, Lys in equilibrium Arg and Ala in equilibrium Gly) can have severe phenotypic effects. Unfortunately, this means that there is no simple way to infer the likely effect of an amino acid substitution on the basis of sequence information alone. A nonconservative Gly----Arg substitution could be phenotypically silent at one position while a conservative Asn----Asp change could lead to complete loss of activity at another position. For proteins whose structures are known, it is often possible to predict whether particular residue substitutions will be destabilizing, as long as detailed estimates of the destabilization energy are not required. Substitutions that introduce polar groups, large cavities, or overly large side chains into the hydrophobic core are potentially the most destabilizing. Substitutions that disrupt hydrogen bonding or electrostatic interactions can also have significant effects, although the destabilization caused by these substitutions is smaller than that caused by severe core mutations. Destabilizing substitutions that involve replacing glycines in turns, or introducing prolines into alpha-helices and other disallowed positions are also reasonably common. Finally, most solvent exposed residues can apparently be freely substituted without serious effects on protein stability. Although exceptions may occur, these generalizations serve to summarize a large body of information and can be rationalized in physical and chemical terms. It is an especially encouraging result that proteins appear to tolerate most substitutions, even those that are destabilizing, without significant changes in the native structure. For proteins whose structures are known, this means that it is reasonable to interpret mutant phenotypes in terms of the wild-type structure. For proteins whose structures are not known, it is reasonable to infer that mutations that reduce activity without affecting stability are directly involved in function.(ABSTRACT TRUNCATED AT 400 WORDS)
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0066-4197
pubmed:author
pubmed:issnType
Print
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
289-310
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1989
pubmed:articleTitle
Genetic analysis of protein stability and function.
pubmed:affiliation
Division of Biology, California Institute of Technology, Pasadena 91125.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Review, Research Support, Non-U.S. Gov't