6otn
From Proteopedia
Crystal Structure of an N-terminal Fragment of Cancer Associated Tropomyosin 3.1 (Tpm3.1)
Structural highlights
DiseaseTPM3_HUMAN Childhood-onset nemaline myopathy;Cap myopathy;Congenital fiber-type disproportion myopathy;Inflammatory myofibroblastic tumor;Intermediate nemaline myopathy;Congenital generalized hypercontractile muscle stiffness syndrome. The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving TPM3 is found in papillary thyroid carcinomas (PTCs). A rearrangement with NTRK1 generates the TRK fusion transcript by fusing the amino end of isoform 2 of TPM3 to the 3'-end of NTRK1.[1] The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionTPM3_HUMAN Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.[UniProtKB:P09493] Publication Abstract from PubMedTropomyosins (Tpm) determine the functional capacity of actin filaments in an isoform-specific manner. The primary isoform in cancer cells is Tpm3.1 and compounds that target Tpm3.1 show promising results as anti-cancer agents both in vivo and in vitro. We have determined the molecular mechanism of interaction of the lead compound ATM-3507 with Tpm3.1-containing actin filaments. When present during co-polymerization of Tpm3.1 with actin, (3)H-ATM-3507 is incorporated into the filaments and saturates at approximately one molecule per Tpm3.1 dimer and with an apparent binding affinity of approximately 2 microM. In contrast, (3)H-ATM-3507 is poorly incorporated into preformed Tpm3.1/actin co-polymers. CD spectroscopy and thermal melts using Tpm3.1 peptides containing the C-terminus, the N-terminus, and a combination of the two forming the overlap junction at the interface of adjacent Tpm3.1 dimers, show that ATM-3507 shifts the melting temperature of the C-terminus and the overlap junction, but not the N-terminus. Molecular dynamic simulation (MDS) analysis predicts that ATM-3507 integrates into the 4-helix coiled coil overlap junction and in doing so, likely changes the lateral movement of Tpm3.1 across the actin surface resulting in an alteration of filament interactions with actin binding proteins and myosin motors, consistent with the cellular impact of ATM-3507. Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1.,Janco M, Rynkiewicz MJ, Li L, Hook J, Eiffe E, Ghosh A, Bocking T, Lehman WJ, Hardeman EC, Gunning PW Sci Rep. 2019 Aug 2;9(1):11262. doi: 10.1038/s41598-019-47592-9. PMID:31375704[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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