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The Notch receptor and its ligands are key components in a core metazoan signaling pathway that regulates the spatial patterning, timing and outcome of many cell-fate decisions. Ligands contain a disulfide-rich Delta/Serrate/LAG-2 (DSL) domain required for Notch trans-activation or cis-inhibition. Here we report the X-ray structure of a receptor binding(More)
Fibrillins and LTBPs [latent TGFβ (transforming growth factor β)-binding proteins] perform vital and complex roles in the extracellular matrix and are relevant to a wide range of human diseases. These proteins share a signature 'eight cysteine' or 'TB (TGFβ-binding protein-like)' domain that is found nowhere else in the human proteome, and which has been(More)
Elastic fibers consist primarily of an amorphous elastin core associated with microfibrils, 10-12 nm in diameter, containing fibrillins and microfibril-associated glycoproteins (MAGPs). To investigate the interaction of MAGP-1 with tropoelastin and fibrillin-1, we expressed human MAGP-1 as a T7-tag fusion protein in Escherichia coli. Refolding of the(More)
The largest group of disease-causing mutations affecting calcium-binding epidermal growth factor-like (cbEGF) domain function in a wide variety of extracellular and transmembrane proteins is that which results in cysteine substitutions. Although known to introduce proteolytic susceptibility, the detailed structural consequences of cysteine substitutions in(More)
The fibrillins and latent transforming growth factor-beta binding proteins (LTBPs) form a superfamily of structurally-related proteins consisting of calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with 8-cysteine-containing transforming growth factor beta-binding protein-like (TB) and hybrid (hyb) domains. Fibrillins are the major(More)
Human fibrillin-1 is the major structural protein of extracellular matrix 10-12 nm microfibrils. It has a disulfide-rich modular organization which consists primarily of cbEGF (Ca(2+)-binding epidermal growth factor-like) domains and TB (transforming growth factor beta-binding protein-like) domains. TB4 contains an RGD (Arg-Gly-Asp) integrin-binding motif.(More)
Force-bearing tissues such as blood vessels, lungs, and ligaments depend on the properties of elasticity and flexibility. The 10 to 12 nm diameter fibrillin microfibrils play vital roles in maintaining the structural integrity of these highly dynamic tissues and in regulating extracellular growth factors. In humans, defective microfibril function results in(More)
Coacervation of soluble tropoelastin molecules is characterized by thermodynamically reversible association as temperature is increased under appropriately juxtaposed ionic conditions, protein concentration and pH. Coacervation plays a critical role in the assembly of these elastin precursors in elastic fiber formation. To examine the effect of(More)
Fibrillin microfibrils are 10-12 nm diameter, extracellular matrix assemblies that provide dynamic tissues of metazoan species with many of their biomechanical properties as well as sequestering growth factors and cytokines. Assembly of fibrillin monomers into microfibrils is thought to occur at the cell surface, with initial steps including proprotein(More)
The calcium-binding epidermal growth factor-like (cbEGF) domain is a common structural motif in extracellular and transmembrane proteins. K(d) values for Ca2+ vary from the millimolar to nanomolar range; however the molecular basis for this variation is poorly understood. We have measured K(d) values for six fibrillin-1 cbEGF domains, each preceded by a(More)