2nzi
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Titin forms an intrasarcomeric filament system in vertebrate striated | + | 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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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Cardiomyopathy, dilated, 1G OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]], Cardiomyopathy, familial hypertrophic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]], Muscular dystrophy, limb-girdle, type 2J OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]], Myopathy, early-onset, with fatal cardiomyopathy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]], Myopathy, proximal, with early respiratory muscle involvement OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]], Tibial muscular dystrophy, tardive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188840 188840]] | ||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==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 Jan 10 | + | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17215480 17215480] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
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[[Category: Labeit, S.]] | [[Category: Labeit, S.]] | ||
[[Category: Mayans, O.]] | [[Category: Mayans, O.]] | ||
| - | [[Category: Mrosek, M | + | [[Category: Mrosek, M C.]] |
[[Category: fniii-domain]] | [[Category: fniii-domain]] | ||
[[Category: ig-domain]] | [[Category: ig-domain]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:12:55 2008'' |
Revision as of 16:13, 21 February 2008
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Crystal structure of domains A168-A170 from titin
Contents |
Overview
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.
Disease
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, 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. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 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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