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JP-2

Domain

The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, by interacting with phospholipids (PubMed:24001019). Has affinity for phosphatidylserine, and phosphorylated phosphatidylinositols including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P2 and PtdIns(3,4,5)P3 (PubMed:24001019).

Junctophilin-2 N-terminal fragment

The bipartite nuclear localization signal (bNLS) and Ala-rich (alanine-rich; ARR) regions are involved in DNA-binding.

Function

Junctophilin-2

Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes (PubMed:20095964). Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads (By similarity). Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release (By similarity). Contributes to the construction of skeletal muscle triad junctions (By similarity).

Junctophilin-2 N-terminal fragment

Transcription repressor required to safeguard against the deleterious effects of cardiac stress. Generated following cleavage of the Junctophilin-2 chain by calpain in response to cardiac stress in cardiomyocytes. Following cleavage and release from the membrane, translocates to the nucleus, binds DNA and represses expression of genes implicated in cell growth and differentiation, hypertrophy, inflammation and fibrosis. Modifies the transcription profile and thereby attenuates pathological remodeling in response to cardiac stress. Probably acts by competing with MEF2 transcription factors and TATA-binding proteins.

Involvement in disease

Cardiomyopathy, familial hypertrophic 17

CMH17

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylation on Ser-165, probably by PKC, affects RYR1-mediated calcium ion release, interaction with TRPC3, and skeletal muscle myotubule development.

Proteolytically cleaved by calpain in response to cardiac stress. The major cleavage site takes place at the C-terminus and leads to the release of the Junctophilin-2 N-terminal fragment chain (JP2NT).

Sequence similarities

Belongs to the junctophilin family.

Tissue specificity

Specifically expressed in skeletal muscle and heart.

Cellular localization

  • Junctophilin-2
  • Cell membrane
  • Peripheral membrane protein
  • Sarcoplasmic reticulum membrane
  • Single-pass type IV membrane protein
  • Endoplasmic reticulum membrane
  • Single-pass type IV membrane protein
  • The transmembrane domain is anchored in sarcoplasmic reticulum membrane, while the N-terminal part associates with the plasma membrane. In heart cells, it predominantly associates along Z lines within myocytes. In skeletal muscle, it is specifically localized at the junction of A and I bands.
  • Junctophilin-2 N-terminal fragment
  • Nucleus
  • Accumulates in the nucleus of stressed hearts.

Alternative names

  • Junctophilin-2
  • JP-2
  • Junctophilin type 2
  • JPH2
  • JP2

Target type

Proteins

Molecular weight

74222Da