Structural organization of the human MS4A gene cluster on Chromosome 11q12

Abstract

CD20, the high-affinity IgE receptor beta chain (FcepsilonRIbeta), and HTm4 are structurally related cell surface proteins expressed by hematopoietic cells. Recently, 16 novel human and mouse genes were identified that encode new members of this nascent protein family that we have named the membrane-spanning 4A gene family, with at least 12 subgroups (MS4A1-MS4A12). In the current study, we identified three additional human MS4A genes: MS4A4E, MS4A6E, and MS4A10. All family members have at least four potential transmembrane domains and N- and C-terminal cytoplasmic domains encoded by distinct exons, except MS4A6E which contains two transmembrane domains. Otherwise, the 12 currently identified MS4A genes share common structural features and similar intron/exon splice boundaries, and are clustered along an approximately 600-kb region of Chromosome 11q12. In contrast to other MS4A genes, MS4A4E, MS4A6E, and MS4A10 transcripts were rare and not detected among hematopoietic cells and most nonlymphoid tissues. Sequence polymorphisms were identified in the MS4A6E gene and common splice variants were observed for the MS4A4A, MS4A5, MS4A6A, and MS4A7 genes. Thus, the MS4A family currently includes 24 distinct human and mouse genes. Like CD20 and FcepsilonRIbeta, the 10 other human MS4A family members are likely to be components of oligomeric cell surface complexes involved in signal transduction in diverse cell lineages.

Binding of HTm4 to Cyclin-dependent Kinase (Cdk)-associated Phosphatase (KAP)·Cdk2·Cyclin A Complex Enhances the Phosphatase Activity of KAP, Dissociates Cyclin A, and Facilitates KAP Dephosphorylation of Cdk2

“…Topologically, this structure provides two tails that are available for protein-protein interactions (2). HTm4 localizes to the nuclear membrane.…”

“…However, a diverse functionality is beginning to emerge. These functions include roles such as cell surface signaling receptors and intracellular adapter proteins (1)(2)(3)(4)(5)22).…”

Characterization of novel murine anti-CD20 monoclonal antibodies and their comparison to 2B8 and c2B8 (rituximab)

“…The precise function of CD20 is unknown and it has been reported to act as an ion channel expressed in the plasma membrane of normal and malignant B cells. Liang et al have reported that CD20 may operate as a calcium storage channel facilitating entry of intracellular calcium following BCR-induced emptying of intracellular calcium (4). The importance of CD20 as a target for mAb immunotherapy is irrefutable, and anti-CD20 monoclonal antibodies appear to be ideal for B-cell diseases.…”

“…It spans the plasma membrane four times and both C-and N-termini are contained within the cell (3)(4)(5)(6). The precise function of CD20 is unknown and it has been reported to act as an ion channel expressed in the plasma membrane of normal and malignant B cells.…”

Targeting CD20 in chronic lymphocytic leukemia

“…7 CD20, which contains both an N and C terminus within the cell, is a member of the MS4A protein group. [8][9][10] CD20 is comprised of two extracellular loops, of which the larger component is made up of 44 amino acids. Rituximab was the first mouse-human chimeric antibody clinically developed to target CD20 and acts through multiple different mechanisms, including complement-mediated cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and direct toxicity.…”