title: Localization of the binding interface between leiomodin-2 and α-tropomyosin.
abstract: The development of some familial dilated cardiomyopathies (DCM) correlates with the presence of mutations in proteins that regulate the organization and function of thin filaments in cardiac muscle cells. Harmful effects of some mutations might be caused by disruption of yet uncharacterized protein-protein interactions. We used nuclear magnetic resonance spectroscopy to localize the region of striated muscle α-tropomyosin (Tpm1.1) that interacts with leiomodin-2 (Lmod2), a member of tropomodulin (Tmod) family of actin-binding proteins. We found that 21 N-terminal residues of Tpm1.1 are involved in interactions with residues 7-41 of Lmod2. The K15N mutation in Tpm1.1, known to be associated with familial DCM, is located within the newly identified Lmod2 binding site of Tpm1.1. We studied the effect of this mutation on binding Lmod2 and Tmod1. The mutation reduced binding affinity for both Lmod2 and Tmod1, which are responsible for correct lengths of thin filaments. The effect of the K15N mutation on Tpm1.1 binding to Lmod2 and Tmod1 provides a molecular rationale for the development of familial DCM.
authors.affiliation: Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164-6515, USA.
authors.forename: Mert
authors.initials: M
authors.lastname: Colpan
authors.affiliation: Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164-6515, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Tolkatchev
authors.affiliation: Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164-6515, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Grover
authors.affiliation: The Center for NMR Spectroscopy, Washington State University, Pullman, WA 99164-4630, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Helms
authors.affiliation: Fundamental & Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Cort
authors.affiliation: Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164-6515, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Moroz
authors.affiliation: Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164-6515, USA. Electronic address: alla.kostyukova@wsu.edu.
authors.forename: Alla S
authors.initials: AS
authors.lastname: Kostyukova
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence / Q000235:genetics; D001665:Binding Sites; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002942:Circular Dichroism; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054792:Muscle, Striated / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051348:Tropomodulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C528309:LMOD2 protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; C490775:TPM1 protein, human; D051348:Tropomodulin; D014335:Tropomyosin
keywords: Circular dichroism; Dilated cardiomyopathy; Intrinsically disordered regions; Leiomodin; Nuclear magnetic resonance; Tropomodulin