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Ca2+ binding by dom...
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Nag, Shalini
(författare)
Ca2+ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin.
- Artikel/kapitelEngelska2009
Förlag, utgivningsår, omfång ...
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2009-08-18
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Proceedings of the National Academy of Sciences,2009
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-411103
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-411103URI
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https://doi.org/10.1073/pnas.0812374106DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Ma, Qing
(författare)
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Wang, Hui
(författare)
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Chumnarnsilpa, Sakesit
(författare)
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Lee, Wei Lin
(författare)
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Larsson, Mårten
(författare)
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Kannan, Balakrishnan
(författare)
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Hernandez-Valladares, Maria
(författare)
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Burtnick, Leslie D
(författare)
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Robinson, Robert C
(författare)
Sammanhörande titlar
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Ingår i:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences106:33, s. 13713-80027-84241091-6490
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