NKF1 family was originally defined in the human genome file as "new kinase family 1". This family is found in most animals, but no member has good characteristics.

Evolution

NKF1 is found in most animals and flagellates. Three members were found in humans: SBK, SgK069 and SgK110

Functions

SBK (SH3-binding domain kinase) was found to be one of the interacting partners of the Fas SH3 domain and is a rich transcript in the rat brain. It has recently been shown to be a survival factor for ovarian cancer cell lines and is abnormally expressed in cancer. Cosmic reports two types of cancer mutations in SBK1 and no mutations in SBK2 (SgK069/SgK110) through large-scale resequencing. Xenopus homologs (Pk9.7, also known as SBK1, although probably not true orthologs) have been reported to be expressed only during blastocyst and gastrointestinal development and involve microtubule control. Among the two fruit fly homologs, CG11221 is uncharacterized, while CG4595 has some high-throughput data. It is selectively expressed in the brain. Worm genes C01C4.3 are also not characteristic.

SH3 domain

The SRC homology 3 domain (or SH3 domain) is a small protein domain of approximately 60 amino acid residues. Originally, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in molecules of phospholipase and several cytosolic tyrosine kinases such as Abl and Src. It has also been found in several other protein families, such as: PI3 kinase, Ras GTPase activating protein, CDC24 and cdc25.SH3 domains are present in signaling pathway proteins that regulate the cytoskeleton.

Figure 1. Ribbon diagram of the SH3 domain.

Structure of SH domain

The SH3 domain has a characteristic β-barrel fold, consisting of five or six β strands, arranged in two closely packed anti-parallel β folds. The linker region may contain a short helix. SH3-type folds are ancient folds found in eukaryotes and prokaryotes.

Peptide binding

Classical SH3 domains are usually found in proteins that interact with other proteins and mediate the assembly of specific protein complexes, usually by binding of the respective proline-binding peptides in their respective binding partners. In humans, the classical SH3 domain is limited to intracellular proteins, although the small human MIA extracellular protein family also contains domains with SH3-like folds.

Many SH3 binding epitopes of proteins have consensus sequences and can be expressed as regular expressions or short linear motifs:

Figure 2. consensus sequences of SH3 binding epitopes.

Wherein 1 and 4 are aliphatic amino acids, 2 and 5 are always 3, and sometimes proline. This sequence binds to the hydrophobic pocket of the SH3 domain. Recently, the SH3 domain that binds to the core consensus motif R-x-x-K has been described. Examples are the C-terminal SH3 domains of adapter proteins such as Grb2 and Mona (aka Gads, Grap2, Grf40, GrpL, etc.). Other SH3 binding motifs have emerged and are still emerging during various molecular studies, highlighting the versatility of this domain.

Reference

1. Koch CA; et al. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991, 252 (5006): 668-74.