12 research outputs found
The interaction of Thrombospondins with extracellular matrix proteins
The thrombospondins (TSPs) are a family of five matricellular proteins that appear to function as adapter molecules to guide extracellular matrix synthesis and tissue remodeling in a variety of normal and disease settings. Various TSPs have been shown to bind to fibronectin, laminin, matrilins, collagens and other extracellular matrix (ECM) proteins. The importance of TSP-1 in this context is underscored by the fact that it is rapidly deposited at the sites of tissue damage by platelets. An association of TSPs with collagens has been known for over 25Β years. The observation that the disruption of the TSP-2 gene in mice leads to collagen fibril abnormalities provided important in vivo evidence that these interactions are physiologically important. Recent biochemical studies have shown that TSP-5 promotes collagen fibril assembly and structural studies suggest that TSPs may interact with collagens through a highly conserved potential metal ion dependent adhesion site (MIDAS). These interactions are critical for normal tissue homeostasis, tumor progression and the etiology of skeletal dysplasias
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Structural Studies of the Elongation Cycle of Protein Synthesis and Its Inhibition by Antibiotics
Protein synthesis takes place in four stages: initiation, elongation, termination and recycling. Elongation consists of delivery of a charged tRNA to the ribosome, peptide bond formation and translocation of the mRNA and tRNA, three steps forming a cyclic process, which is repeated for every amino acid added to a growing polypeptide chain. The result of the elongation cycle is the translation of the triplet genetic code contained in an mRNA, into the amino acid sequence of a protein. Since the 1960s it was appreciated that complex conformational changes must occur on the ribosome to accomplish translocation of mRNA and tRNA. Here I report x-ray crystallographic studies which shed light on how mRNA and tRNA are manipulated by the ribosome and mechanisms used by certain antibiotics to inhibit the elongation cycle of protein synthesis.Specifically research reported here argue that tRNA translocation is a stepwise process that involves discrete structural intermediates of the ribosome. I report structural evidence that the antibiotics clindamycin and chloramphenicol inhibit protein synthesis by interfering with aminoacyl-tRNA positioning in the peptidyl transferase center. Also, I hypothesize based on structural data and phylogenetic analysis, that the identity of the ribosomal RNA residues numbered in E. coli 752, 2055 and 2609 contribute to the specificity of many antibiotics for binding to bacterial, rather than archaeal or eukaryotic ribosomes