Linked Life Data

21216247

Source:http://linkedlifedata.com/resource/pubmed/id/21216247

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-2-7
pubmed:abstractText
Otoferlin (Otof), whose genetic mutations cause profound deafness in humans, is a protein composed of at least six C(2) domains, which are known as Ca(2)(+)-binding and phospholipid-binding regions. Mammalian ferlin proteins are proposed to act in membrane fusion events, with Otof being specifically required for exocytosis in auditory hair cells. Ferlin C(2) domains exhibit a rather low level of sequence similarity to those of synaptotagmins, protein kinase C isoforms, or phospholipases. Here, we report the crystal structure of the N-terminal C(2) domain of Otof (C?A) at 1.95-Å resolution. In contrast to previous predictions, we found that this C(2) domain is complete with eight ?-strands. Comparing the structure of Otof C?A to those of other C(2) domains revealed one top loop in Otof to be significantly shorter. This results in a depression of the surface, which is positively charged for the Otof C?A domain, and contrasts with the head-like protrusion surrounded by a negatively charged "neck" typically found in other C(2) domains. Isothermal titration calorimetry and circular dichroism spectroscopy studies confirmed that Otof C?A is unable to bind Ca(2+), while the synaptotagmin-1 C?A domain exhibited Ca(2+) binding under the same conditions. Furthermore, floatation assays revealed a failure of Otof C(2)A to bind to phospholipid membranes. Accordingly, no positively charged ?-groove-like surface structure, which is known to bind phosphatidylinositol-4,5-bisphosphate in other C(2) domains, was found at the respective position in Otof C?A. Taken together, these data demonstrate that the Otof C?A domain differs structurally and functionally from other C(2) domains.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1089-8638
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
25
pubmed:volume
406
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
479-90
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
The crystal structure of the C?A domain of otoferlin reveals an unconventional top loop region.
pubmed:affiliation
Molecular Biology of Cochlear Neurotransmission Junior Research Group, University Medical Center Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't