Solution structure of the LDL receptor EGF-AB pair: A paradigm for the assembly of tandem calcium binding EGF domains

Background: From the observed structure and sequence of a pair of calcium b inding (cb) epidermal growth factor-like (EGF) domains from human fibrillin -1, we proposed that many tandem cbEGF domains adopt a conserved relative c onformation. The low-density lipoprotein receptor (LDLR), which is function ally unrelated to fibrillin-1, contains a single pair of EGF domains that w as chosen for study in the validation of this hypothesis. The LDLR is the p rotein that is defective in familiar hypercholesterolaemia, a common geneti c disorder that predisposes individuals to cardiovascular complications and premature death. Results: Here, we present the solution structure of the first two EGF domai ns from the LDL receptor, determined using conventional NMR restraints and residual dipolar couplings. The cbEGF domains have an elongated, rod-like a rrangement, as predicted. The new structure allows a detailed assessment of the consequences of mutations associated with familial hypercholesterolaem ia to be made. Conclusions: The validation of the conserved arrangement of EGF domains in functionally distinct proteins has important implications for structural ge nomics, since multiple tandem cbEGF pairs have been identified in many esse ntial proteins that are implicated in human disease. Our results provide th e means to use homology modeling to probe structure-function relationships in this diverse family of proteins and may hold the potential for the desig n of novel diagnostics and therapies in the future.