Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy

Zhou, Qiang; Chu, Pao‐Hsien; Huang, Cai; Cheng, Ching Feng; Martone, Maryann E.; Knoll, Gertrud; Shelton, G. Diane; Evans, Sylvia M.; Chen, J

doi:10.1083/jcb.200107092

Cited by 252 publications

(271 citation statements)

References 25 publications

(40 reference statements)

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“…Organization of each of these structures is essential for proper functioning of the sarcomere and their perturbation can lead to malfunctioning of cardiac tissue. Several studies have linked cytoskeletal proteins to cardiomyopathy such as the Z-disc proteins ALP and ZASP/cypher [49,50], the membrane-associated cytoskeletal proteins dystrophin [51] and sarcoglycans [52], and the intermediate filament component desmin [53].…”

Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calciumregulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.

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Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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“…We would also predict that ZASP/ Cypher would have similar interaction sites with ␣-actinin and, thus, similar function. The ZASP/Cypher knockout mice have even more severe cardiomyopathy and muscle dystrophy phenotypes than the ALP mice (24). The differences in ALP and ZASP/Cypher phenotypes may mirror their specific functions in different muscle types.…”

Section: Discussionmentioning

confidence: 98%

“…Manner-Because ALP is localized at the Z-lines in differentiated muscle cells and the ALP and ZASP/Cypher gene depletion in mice may abrogate Z-line stability or turnover (24,26), we wanted to study the requirement of the two interaction sites also in the Z-line localization. GFP constructs of ALP were transfected to mouse C2C12 myoblasts.…”

Section: Skeletal and Smooth Muscle Alp Localize To Z-lines In A Similarmentioning

confidence: 99%

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The ZASP-like Motif in Actinin-associated LIM Protein Is Required for Interaction with the α-Actinin Rod and for Targeting to the Muscle Z-line

Klaavuniemi

Kelloniemi

Ylänne

2004

Journal of Biological Chemistry

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The Z-line is a specialized structure connecting adjacent sarcomeres in muscle cells. ␣-Actinin cross-links actin filaments in the Z-line. Several PDZ-LIM domain proteins localize to the Z-line and interact with ␣-actinin. Actinin-associated LIM protein (ALP), C-terminal LIM domain protein (CLP36), and Z band alternatively spliced PDZ-containing protein (ZASP) have a conserved region named the ZASP-like motif (ZM) between PDZ and LIM domains. To study the interactions and function of ALP we used purified recombinant proteins in surface plasmon resonance measurements. We show that ALP and ␣-actinin 2 have two interaction sites. The ZM motif was required for the interaction of ALP internal region with the ␣-actinin rod and for targeting of ALP to the Z-line. The PDZ domain of ALP bound to the C terminus of ␣-actinin. This is the first indication that the ZM motif would have a direct role in a proteinprotein interaction. These results suggest that the two interaction sites of ALP would stabilize certain conformations of ␣-actinin 2 that would strengthen the Z-line integrity.The muscle Z-line is a highly specialized structure between adjacent sarcomeres in muscle fibers that maintain the organization of the contractile machinery (for review, see Ref. 1). ␣-Actinin is one of the major components at the Z-line. The ␣-actinin polypeptide is composed of an N-terminal actin binding domain, four spectrin repeats that form the central rod region (2, 3), and two pairs of C-terminal EF-hands (4). ␣-Actinin forms an antiparallel homodimer. ␣-Actinin cross-links actin filaments from opposite sarcomeres to the Z-line and, therefore, has a major mechanical function in keeping the sarcomeres together.Several PDZ-LIM proteins have been detected in the muscle Z-line and shown to interact with ␣-actinin (5-12). PDZ domain is a widely expressed protein-protein interaction domain (for review, see Ref. 13). PDZ-LIM proteins form one subgroup of PDZ proteins (13) and are regarded as mediators between cytoskeletal structures and signaling cascades.PDZ-LIM proteins can be divided in two subclasses; they either contain one or three LIM domains. Actinin-associated LIM protein (ALP) 1 (5, 10), C-terminal LIM domain protein (CLP36) (14) (also called hCLIM1 (15) or Elfin (16)), Reversion-induced LIM protein (RIL) (17), and Mystique (Uniprot accession number Q7Z584) belong to the first class, which has one N-terminal PDZ domain and one C-terminal LIM domain. ALP is expressed in muscle (5, 10), whereas CLP36 and RIL are mainly expressed in nonmuscle tissues (11,18,19). CLP36 shows also high expression levels in muscle (7,15,16). Enigma, Enigma homology protein, and ZASP/Cypher/Oracle form the second class, with one N-terminal PDZ domain and three C-terminal LIM domains. They all are expressed mainly in muscle (6, 9, 20 -22). An interesting feature of these seven PDZ-LIM proteins is that ALP, CLP36, and ZASP contain a conserved region, named ZASP-like motif (ZM) (SMART prediction (23) accession number SM 00735, Interpro 006643), in the internal r...

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“…Most members of this group colocalize with ␣-actinin in the Z-disks of striated and cardiac muscles and in intercalated disks of cardiac muscles. The interactions of PDZ-LIM domain proteins with ␣-actinin provide tensile integrity to the Z-disk, since mice ablated for Cypher, an Enigma-family protein, exhibit muscle defects with disrupted Z-disks and early postnatal death due to respiratory failure (Zhou et al, 2001). An attractive model suggests that their binding to ␣-actinin may fine tune the actin cross-linking property of ␣-actinin and this hypothesis is supported by research demonstrating that addition of ALP to an ␣-actininactin mixture significantly enhances their co-sedimentation in vitro (Pashmforoush et al, 2001).…”

Section: The Z-disk As a Focal Point For Force Propagationmentioning

confidence: 99%

Molecular mechanisms of mechanosensing in muscle development

Jani

Schöck

2009

Developmental Dynamics

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Mechanical forces are crucial to muscle development and function, but the mechanisms by which forces are sensed and transduced remain elusive. Evidence implicates the sarcolemmal lattice of integrin adhesion and the Z-disk components of the contractile machinery in such processes. These mechanosensory devices report changes in force to other cellular compartments by self-remodeling. Here we explore how their structural and functional properties integrate to regulate muscle development and maintenance.

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Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy

Cited by 252 publications

References 25 publications

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

The ZASP-like Motif in Actinin-associated LIM Protein Is Required for Interaction with the α-Actinin Rod and for Targeting to the Muscle Z-line

Molecular mechanisms of mechanosensing in muscle development

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