2nzi
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Crystal structure of domains A168-A170 from titin
OverviewOverview
Titin forms an intrasarcomeric filament system in vertebrate striated, muscle, which has elastic and signaling properties and is thereby central, to mechanotransduction. Near its C-terminus and directly preceding a, kinase domain, titin contains a conserved pattern of Ig and FnIII modules, (Ig(A168)-Ig(A169)-FnIII(A170), hereby A168-A170) that recruits the E3, ubiquitin-ligase MuRF-1 to the filament. This interaction is thought to, regulate myofibril turnover and the trophic state of muscle. We have, elucidated the crystal structure of A168-A170, characterized MuRF-1, variants by cluster of differentiation (CD) and SEC-MALS, and studied the, interaction of both components by isothermal calorimetry, SPOTS blots, and, pull-down assays. This has led to the identification of the molecular, determinants of the binding. A168-A170 shows an extended, rigid, architecture, which is characterized by a shallow surface groove that, spans its full length and a distinct loop protrusion in its middle point., In MuRF-1, a C-terminal helical domain is sufficient to bind A168-A170, with high affinity. This helical region predictably docks into the surface, groove of A168-A170. Furthermore, pull-down assays demonstrate that the, loop protrusion in A168-A170 is a key mediator of MuRF-1 recognition. Our, findings indicate that this region of titin could serve as a target to, attempt therapeutic inhibition of MuRF-1-mediated muscle turnover, where, binding of small molecules to its distinctive structural features could, block MuRF-1 access.--Mrosek, M., Labeit, D., Witt, S., Heerklotz, H., von, Castelmur, E., Labeit, S., Mayans, O. Molecular determinants for the, recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin.
DiseaseDisease
Known diseases associated with this structure: Cardiomyopathy, dilated, 1G OMIM:[188840], Cardiomyopathy, familial hypertrophic OMIM:[188840], Muscular dystrophy, limb-girdle, type 2J OMIM:[188840], Myopathy, proximal, with early respiratory muscle involvement OMIM:[188840], Tibial muscular dystrophy, tardive OMIM:[188840]
About this StructureAbout this Structure
2NZI is a Single protein structure of sequence from Homo sapiens. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin., Mrosek M, Labeit D, Witt S, Heerklotz H, von Castelmur E, Labeit S, Mayans O, FASEB J. 2007 Jan 10;. PMID:17215480
Page seeded by OCA on Mon Nov 12 23:04:41 2007