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rdf:type |
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lifeskim:mentions |
umls-concept:C0032214,
umls-concept:C0035820,
umls-concept:C0061187,
umls-concept:C0596235,
umls-concept:C0600138,
umls-concept:C1167622,
umls-concept:C1511545,
umls-concept:C1514562,
umls-concept:C1879547,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221
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pubmed:issue |
33
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pubmed:dateCreated |
2009-8-26
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pubmed:abstractText |
Gelsolin consists of six homologous domains (G1-G6), each containing a conserved Ca-binding site. Occupation of a subset of these sites enables gelsolin to sever and cap actin filaments in a Ca-dependent manner. Here, we present the structures of Ca-free human gelsolin and of Ca-bound human G1-G3 in a complex with actin. These structures closely resemble those determined previously for equine gelsolin. However, the G2 Ca-binding site is occupied in the human G1-G3/actin structure, whereas it is vacant in the equine version. In-depth comparison of the Ca-free and Ca-activated, actin-bound human gelsolin structures suggests G2 and G6 to be cooperative in binding Ca(2+) and responsible for opening the G2-G6 latch to expose the F-actin-binding site on G2. Mutational analysis of the G2 and G6 Ca-binding sites demonstrates their interdependence in maintaining the compact structure in the absence of calcium. Examination of Ca binding by G2 in human G1-G3/actin reveals that the Ca(2+) locks the G2-G3 interface. Thermal denaturation studies of G2-G3 indicate that Ca binding stabilizes this fragment, driving it into the active conformation. The G2 Ca-binding site is mutated in gelsolin from familial amyloidosis (Finnish-type) patients. This disease initially proceeds through protease cleavage of G2, ultimately to produce a fragment that forms amyloid fibrils. The data presented here support a mechanism whereby the loss of Ca binding by G2 prolongs the lifetime of partially activated, intermediate conformations in which the protease cleavage site is exposed.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-11707399,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-11753432,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-11788061,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-12460571,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-12655044,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-12742020,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-12966145,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-1338910,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-14527664,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-15215896,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-15526166,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-16281052,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-16466744,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-16469333,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-16475811,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-17604278,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-1849145,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-2334416,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-2828382,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-2850369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-6325429,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-7849017,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-9003812,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-9288746,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-9323209,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-9398317,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19666512-9490033
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1091-6490
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
18
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pubmed:volume |
106
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13713-8
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:19666512-Actins,
pubmed-meshheading:19666512-Amyloid,
pubmed-meshheading:19666512-Animals,
pubmed-meshheading:19666512-Binding Sites,
pubmed-meshheading:19666512-Calcium,
pubmed-meshheading:19666512-DNA Mutational Analysis,
pubmed-meshheading:19666512-Enzyme Activation,
pubmed-meshheading:19666512-Gelsolin,
pubmed-meshheading:19666512-Horses,
pubmed-meshheading:19666512-Humans,
pubmed-meshheading:19666512-Mutation,
pubmed-meshheading:19666512-Peptide Hydrolases,
pubmed-meshheading:19666512-Protein Binding,
pubmed-meshheading:19666512-Protein Conformation,
pubmed-meshheading:19666512-Species Specificity
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pubmed:year |
2009
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pubmed:articleTitle |
Ca2+ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin.
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pubmed:affiliation |
Institute of Molecular and Cell Biology, ASTAR, 61 Biopolis Drive, Proteos, Singapore 138673.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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