ZAP-70

ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein that plays a critical role in the immune system, particularly in the signaling pathways of T cells. It is a member of the protein-tyrosine kinase family and is encoded by the ZAP70 gene in humans.

Structure

ZAP-70 is a 70 kDa protein that consists of several domains, including two SH2 domains and a kinase domain. The SH2 domains are responsible for binding to phosphorylated tyrosine residues on the T-cell receptor (TCR) complex, while the kinase domain is involved in the phosphorylation of downstream signaling molecules.

Function

ZAP-70 is primarily expressed in T cells and natural killer cells. It is a key component of the TCR signaling cascade. Upon antigen recognition, the TCR complex becomes phosphorylated, creating docking sites for ZAP-70. Once recruited to the TCR complex, ZAP-70 becomes activated and phosphorylates several downstream targets, including LAT (linker for activation of T cells) and SLP-76, which further propagate the signal leading to T cell activation, proliferation, and differentiation.

Clinical Significance

Mutations in the ZAP70 gene can lead to immunodeficiency disorders. One such condition is ZAP-70 deficiency, a rare form of severe combined immunodeficiency (SCID) characterized by the absence of CD8+ T cells and non-functional CD4+ T cells, leading to increased susceptibility to infections.

ZAP-70 is also of interest in chronic lymphocytic leukemia (CLL). The expression level of ZAP-70 in CLL cells is used as a prognostic marker. High levels of ZAP-70 expression are associated with a more aggressive form of the disease and poorer prognosis.

Research and Therapeutic Implications

ZAP-70 is a target for therapeutic intervention in autoimmune diseases and certain types of cancer. Inhibitors of ZAP-70 are being investigated for their potential to modulate immune responses and treat diseases characterized by excessive or inappropriate T cell activation.

Also see

• T-cell receptor
• Protein-tyrosine kinase
• Chronic lymphocytic leukemia
• Severe combined immunodeficiency