Myospryn Is a Novel Binding Partner for Dysbindin in Muscle

Benson, Matthew A.; Tinsley, Caroline L.; Blake, Derek J.

doi:10.1074/jbc.m312664200

Cited by 64 publications

(95 citation statements)

References 43 publications

(58 reference statements)

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“…Immunofluorescence microscopy and PLA experiments suggest that the interaction between M-band titin and myospryn takes place primarily at the myofiber periphery. This is in accordance with the predominantly subsarcolemmal localization of myospryn (21). As myospryn has been reported to associate with costameres (23,24), the interaction of titin with myospryn could provide a link between the peripheral myofibrils and the costamere-like structures present at the M-band level (39).…”

Section: Discussionsupporting

confidence: 60%

“…The construct pCMV-Myc-MD7, encoding the 701 C-terminal amino acid residues of mouse myospryn (corresponding to 707 C-terminal amino acids of the human protein) with an N-terminal Myc tag (Myc-MD7), has been described previously (21). The myospryn insert MD9, encoding the 1009 C-terminal amino acids of mouse myospryn (1018 amino acids in human), was PCR-amplified from pCI-Neo-MD9 (21) and cloned into pCR-Blunt II-TOPO.…”

Section: Mammalian Expression Constructs-m-band Titin Con-mentioning

confidence: 99%

“…Myospryn is a large protein (449 kDa; 4069 amino acids in human), comprising a repetitive, acidic N-terminal part and a C-terminal domain structure related to the tripartite motif proteins ( Fig. 1C) (21). Myospryn is specifically expressed in striated muscle (21,22), where it has been suggested to associate with sarcoplasmic reticulum (SR) and costameres (23,24).…”

mentioning

confidence: 99%

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Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Sarparanta

Blandin

Charton

et al. 2010

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 60%

Section: Mammalian Expression Constructs-m-band Titin Con-mentioning

confidence: 99%

mentioning

confidence: 99%

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Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Sarparanta

Blandin

Charton

et al. 2010

Journal of Biological Chemistry

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“…As depicted in Fig. 1B, immunostaining of adult wild type hind limb muscle detected myospryn along the myofiber periphery (see WT-myospryn, upper middle panel) as previously published by our group and others (28,31,32). In striking contrast, mdx muscle exhibited a discontinuous localization of myospryn at the myofiber periphery with extensive regions devoid of myospryn ( Fig.…”

Section: Degradation and Mislocalization Of Myospryn In MDX Muscle-mentioning

confidence: 61%

Deregulated Protein Kinase A Signaling and Myospryn Expression in Muscular Dystrophy

Reynolds

McCalmon

Donaghey

et al. 2008

Journal of Biological Chemistry

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Alterations in signaling pathway activity have been implicated in the pathogenesis of Duchenne muscular dystrophy, a degenerative muscle disease caused by a deficiency in the costameric protein dystrophin. Accordingly, the notion of the dystrophin-glycoprotein complex, and by extension the costamere, as harboring signaling components has received increased attention in recent years. The localization of most, if not all, signaling enzymes to this subcellular region relies on interactions with scaffolding proteins directly or indirectly associated with the dystrophin-glycoprotein complex. One of these scaffolds is myospryn, a large, muscle-specific protein kinase A (PKA) anchoring protein or AKAP. Previous studies have demonstrated a dysregulation of myospryn expression in human Duchenne muscular dystrophy, suggesting a connection to the pathophysiology of the disorder. Here we report that dystrophic muscle exhibits reduced PKA activity resulting, in part, from severely mislocalized myospryn and the type II regulatory subunit (RII␣) of PKA. Furthermore, we show that myospryn and dystrophin coimmunoprecipitate in native muscle extracts and directly interact in vitro. Our findings reveal for the first time abnormalities in the PKA signal transduction pathway and myospryn regulation in dystrophin deficiency.The major macromolecular protein complex within the muscle costamere is the dystrophin-glycoprotein complex (DGC). 2The DGC harbors the large, actin-binding protein dystrophin, the absence of which results in Duchenne muscular dystrophy (DMD), a lethal, X-linked degenerative muscle disease (1-4). It is undisputed that defects within the DGC are one of the major triggers of muscular dystrophy, yet the mechanisms by which a defective DGC leads to muscle degeneration remain unclear. Hence, intense efforts have been put forth to molecularly dissect the function of dystrophin as well as the DGC (5, 6) and to identify novel regulators of this complex in striated muscle.Dystrophin serves as a scaffold for numerous protein-protein interactions with components of the DGC as well as non-DGC proteins at the level of the costamere (7, 8). The prevailing model suggests a structural and mechanical role for dystrophin (9), but an additional function in signaling has been proposed (10, 11). Although elucidating the role of dystrophin in signaling has been a challenging task, there is evidence of altered signaling activity in muscular dystrophies. Alterations in calcium levels and the neuronal nitric oxide synthase pathway in DMD have been known for some time (12)(13)(14). Perturbations in the activity of additional signaling molecules such as calcineurin, Akt, JNK1, and IB kinase/ NF-B have been linked to muscular dystrophies (15)(16)(17)(18)(19).Recently, we showed that the costameric protein myospryn functions as a muscle-specific protein kinase A (PKA) anchoring protein or AKAP (20). This was the first demonstration of myospryn coordinating the PKA signaling pathway at the level of the costamere. The AKAP family of scaffolding...

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“…Pallidin was reported to interact with Syntaxin 13, a SNARE protein localized to early endosomes and implicated in membrane fusion (28). Dysbindin was originally described as a binding partner of ␣-and ␤-dystrobrevins (two proteins related to the dystrophin protein associated with Duchenne/Becker muscular dystrophy) and recently reported to interact with a novel, muscle-specific protein named Myospryn (30,44). The physiological significance of these interactions remains to be determined.…”

Section: Table I Previously Known and Candidate Bloc-1 Subunits Identmentioning

confidence: 99%

Identification of Snapin and Three Novel Proteins (BLOS1, BLOS2, and BLOS3/Reduced Pigmentation) as Subunits of Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1)

Starcevic¹,

Dell’Angelica

2004

Journal of Biological Chemistry

229

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Biogenesis of lysosome-related organelles complex-1 (BLOC-1) is a ubiquitously expressed multisubunit protein complex required for the normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules. The complex is known to contain the coiled-coil-forming proteins, Pallidin, Muted, Cappuccino, and Dysbindin. The genes encoding these proteins are defective in inbred mouse strains that serve as models of Hermansky-Pudlak syndrome (HPS), a genetic disorder characterized by hypopigmentation and platelet storage pool deficiency. In addition, mutation of human Dysbindin causes HPS type 7. Here, we report the identification of another four subunits of the complex. One is Snapin, a coiled-coilforming protein previously characterized as a binding partner of synaptosomal-associated proteins 25 and 23 and implicated in the regulation of membrane fusion events. The other three are previously uncharacterized proteins, which we named BLOC subunits 1, 2, and 3 (BLOS1, -2, and -3). Using specific antibodies to detect endogenous proteins from human and mouse cells, we found that Snapin, BLOS1, BLOS2, and BLOS3 co-immunoprecipitate, and co-fractionate upon size exclusion chromatography, with previously known BLOC-1 subunits. Furthermore, steady-state levels of the four proteins are significantly reduced in cells from pallid mice, which carry a mutation in Pallidin and display secondary loss of other BLOC-1 subunits. Yeast two-hybrid analyses suggest a network of binary interactions involving all of the previously known and newly identified subunits. Interestingly, the HPS mouse model strain, reduced pigmentation, carries a nonsense mutation in the gene encoding BLOS3. As judged from size exclusion chromatographic analyses, the reduced pigmentation mutation affects BLOC-1 assembly less severely than the pallid mutation. Mutations in the human genes encoding Snapin and the BLOS proteins could underlie novel forms of HPS.

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Myospryn Is a Novel Binding Partner for Dysbindin in Muscle

Cited by 64 publications

References 43 publications

Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Deregulated Protein Kinase A Signaling and Myospryn Expression in Muscular Dystrophy

Identification of Snapin and Three Novel Proteins (BLOS1, BLOS2, and BLOS3/Reduced Pigmentation) as Subunits of Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1)

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