2nzi

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{{STRUCTURE_2nzi| PDB=2nzi | SCENE= }}
{{STRUCTURE_2nzi| PDB=2nzi | SCENE= }}
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'''Crystal structure of domains A168-A170 from titin'''
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===Crystal structure of domains A168-A170 from titin===
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==Overview==
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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 circular dichroism (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.
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(as it appears on PubMed at http://www.pubmed.gov), where 17215480 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17215480}}
==Disease==
==Disease==
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[[Category: Fniii-domain]]
[[Category: Fniii-domain]]
[[Category: Ig-domain]]
[[Category: Ig-domain]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:07:09 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 20:20:22 2008''

Revision as of 17:20, 28 July 2008

Image:2nzi.png

Template:STRUCTURE 2nzi

Contents

Crystal structure of domains A168-A170 from titin

Template:ABSTRACT PUBMED 17215480

Disease

Known disease associated with this structure: Cardiomyopathy, dilated, 1G OMIM:[188840], Cardiomyopathy, familial hypertrophic OMIM:[188840], Muscular dystrophy, limb-girdle, type 2J OMIM:[188840], Myopathy, early-onset, with fatal cardiomyopathy OMIM:[188840], Myopathy, proximal, with early respiratory muscle involvement OMIM:[188840], Tibial muscular dystrophy, tardive OMIM:[188840]

About this Structure

2NZI is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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 May;21(7):1383-92. Epub 2007 Jan 10. PMID:17215480

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