The molecular mechanism of cell adhesion by classical cadherins is now understood at an atomic level ofdetail. However, the basis of desmosomal cadherin function has not yet been determined. This Pilot andFeasibility project is focused on determining the first high-resolution structures of desmosomal cadherins inorder to determine the detailed molecular.basis of their cell adhesive function. The cadherin family ischaracterized by their extracellular cadherin repeat domains (EC1-EC5). It is known that the adhesivefunction of the cadherin extracellular region is dependent upon the binding of calcium ions between each ofthese repeat domains which leads to the rigidification of the entire region, however, the specific interfacesand interactions responsible for adhesion are not clearly understood. Some light was shed on this issuerecently when the crystal structure of the extracellular domain of C-cadherin was solved by our group. Thisstructure revealed that binding between C-cadherins on opposing cell surfaces most likely occurs when aconserved tryptophan (Trp2) residue of a C-cadherin on one cell intercalates into a hydrophobic pocket,containing highly conserved R-A-L residues, of a C-cadherin on an opposing cell. Further, it was noted thatC-cadherins on the same cell surface may interact via a similar mechanism to promote molecular clusteringthereby allowing for enhanced adhesion between cells. Both the Trp2 residue and the hydrophobic bindingpocket are conserved in desmosomal cadherins, therefore, it seems likely that desmogleins anddesmocollins may interact via this same mechanism. However, to date no crystal structure for any of thedesmosomal cadherins has been solved. This led us to hypothesize: What is the structure of the adhesiveinterface of a desmosomal cadherin? How do the adhesive interfaces of desmosomal cadherins interact tocontribute to the formation of desmosomes? In order to gain some understanding about the structure of theextracellular domain of desmosomal cadherins, we have embarked on a collaborative effort with Dr. AngelaChristiano in the Department of Dermatology at Columbia University to crystallize the extracellular domain ofhuman desmogleins. The goal of this Pilot and Feasibility study is to understand the detailed molecularmechanisms of cadherin function in desmosome intercellular junctions.Dr. Shapiro qualifies under eligibility Category #2 in the Guidelines as an Established Investigator with noprevious work in research related to the SDRC. He is an internationally renowned structural biologist whohas resolved the structure of many classical cadherins. In this proposal, he will turn his attention to thedesmosomal cadherins, central players in skin biology. Dr. Shapiro's P&F study utilizes Cores C and D.
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