Our lab specializes in the 3D structure of C2 domains.
Synaptotagmin is the Ca2+ sensor for exocytosis. We have crystallizes the two tandem C2 domains of human synaptotagmin.
This crystal structure shows clear signs of inter-domain interaction.
Fuson KL, Montes M, Robert JJ, Sutton RB. Structure of human synaptotagmin 1 C2AB
in the absence of Ca2+ reveals a novel domain association.Biochemistry. 2007 Nov 13;46(45):13041-8. Epub
2007 Oct 23.
Muscle is unique among the tissues of the body in that its primary function is to
generate mechanical force. These relatively large forces introduce damage in the form
of rips and tears within the membrane of the muscle cells. Without an in vivo repair mechanism, muscle tissue would be unable to function. Dysferlin is a 237kDa
multi-domain protein that is expressed at high levels in skeletal and cardiac muscle
tissue, and appears to play a critical role in resealing tears in the muscle cell
phospholipid membranes. This protein is made up of 7 tandem C2 domains (labeled C2A,
C2B, C2C...) that are distributed along the length of the protein. Mutations within
the dysferlin gene in humans can result in Limb-Girdle muscular dystrophy (LGMD),
presumably resulting from an impaired ability to reseal damaged muscle tissue. To
understand what this protein could be doing at the atomic level, we recently solved
the 2.0Å X-ray crystal structure of the C2A domain of human dysferlin.
Now that we have a high resolution structure of one of these domains, we would like
to establish why point mutations such as V67D produce severe phenotypes in Limb-Girdle
Muscular Dystrophy patients. We hope to one day discover drugs that may stabilize
this mutant C2 domain, to provide some degree of treatment for patients with this
form of muscular dystrophy.
This work has been sponsored exclusively by the Jain Foundation