3sek
From Proteopedia
Crystal Structure of the Myostatin:Follistatin-like 3 Complex
Structural highlights
Disease[FSTL3_HUMAN] Note=A chromosomal aberration involving FSTL3 is found in a case of B-cell chronic lymphocytic leukemia. Translocation t(11;19)(q13;p13) with CCDN1. Function[GDF8_MOUSE] Acts specifically as a negative regulator of skeletal muscle growth. [FSTL3_HUMAN] Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such us activin, BMP2 and MSTN. Inhibits activin A-, activin B-, BMP2- and MSDT-induced cellular signaling; more effective on activin A than on activin B. Involved in bone formation; inhibits osteoclast differentiationc. Involved in hematopoiesis; involved in differentiation of hemopoietic progenitor cells, increases hematopoietic cell adhesion to fibronectin and seems to contribute to the adhesion of hematopoietic precursor cells to the bone marrow stroma. Isoform 2 or the nuclear form is probably involved in transcriptional regulation via interaction with MLLT10.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedTGF-beta family ligands are involved in a variety of critical physiological processes. For instance, the TGF-beta ligand myostatin is a staunch negative regulator of muscle growth and a therapeutic target for muscle-wasting disorders. Therefore, it is important to understand the molecular mechanisms of TGF-beta family regulation. One form of regulation is through inhibition by extracellular antagonists such as the follistatin (Fst)-type proteins. Myostatin is tightly controlled by Fst-like 3 (Fstl3), which is the only Fst-type molecule that has been identified in the serum bound to myostatin. Here, we present the crystal structure of myostatin in complex with Fstl3. The structure reveals that the N-terminal domain (ND) of Fstl3 interacts uniquely with myostatin as compared with activin A, because it utilizes different surfaces on the ligand. This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand. We also show that single point mutations in the ND of Fstl3 are detrimental to ligand binding, whereas corresponding mutations in Fst have little effect. Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand.Fst-type protein complexes. Structure of myostatin.follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding.,Cash JN, Angerman EB, Kattamuri C, Nolan K, Zhao H, Sidis Y, Keutmann HT, Thompson TB J Biol Chem. 2012 Jan 6;287(2):1043-53. Epub 2011 Nov 3. PMID:22052913[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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