Spectrin alpha chain, SH3 domain (IPR013315)

Short name: Spectrin_alpha_SH3

Domain relationships



SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [PMID: 15335710, PMID: 11256992]. They are found in a great variety of intracellular or membrane-associated proteins [PMID: 1639195, PMID: 14731533, PMID: 7531822] for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.

The SH3 domain has a characteristic fold which consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [PMID: 7953536].

This entry is a sub-group of the SH3 domain (IPR001452). Spectrin is an elongated protein that belongs to a family of related molecules (including dystrophin and alpha-actinin) that contain tandemly repeated segments and form resilient cellular meshworks by cross-linking actin filaments [PMID: 8266097]. The protein is an alpha-beta heterodimer [PMID: 6472478] in which the alpha and beta monomers associate in an anti-parallel fashion [PMID: 1634521]. Assembly involves initial contact of complementary nucleation sites on each subunit, via four tandem repeat regions [PMID: 1634521]. Following nucleation, the remainder of the subunits associate rapidly along their full lengths to form a dimer by super-coiling around each other, forming a rope-like, flexible rod [PMID: 1634521]. Assembly terminates if either polypeptide is interrupted by protease cleavage. Heterozygotic mutations involving either nucleation site are predicted to affect allele incorporation into the mature membrane skeleton [PMID: 1634521].

The structure of a repeat unit of alpha-spectrin has been determined to 1.8A resolution by means of X-ray crystallography [PMID: 8266097]. This was shown to comprise an anti-parallel three-helix bundle separated by two loops, which folds into a left-handed coiled coil [PMID: 9356261]. At the interface between tandem repeats, hydrophobic interactions may constrain intersegment flexibility. The interaction between alpha- and beta-subunits is mediated by the association of two helices at the C terminus of the beta-chain and a single helix from the N terminus of the alpha-chain. Mutations that affect these critical helix side-chain interactions disrupt spectrin associations that sustain the integrity of erythrocyte membranes giving rise to haemolytic anaemias [PMID: 8266097, PMID: 9356261]. These haemolytic syndromes include hereditary elliptocytosis, its aggravated form hereditary pyropoikilocytosis and hereditary spherocytosis [PMID: 8844207, PMID: 1878597].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.