The Sp100 protein is a constituent of nuclear domains, also known as nuclear dots (NDs). An ND-targeting region that coincides with a homodimerisation domain was mapped in Sp100. Sequences similar to the Sp100 homodimerization/ND-targeting region occur in several other proteins and constitute a novel protein motif, termed HSR domain (for homogeneously-staining region) []. This domain can also be found in Vertebrate AutoImmune REgulator (AIRE) protein, a transcription regulator predominantly expressed in thymus medullary epithelial cells which also localises to nuclear dots []. The HSR domain, which has also been named ASS (AIRE, Sp-100 and Sp140) domain [], can be found alone or in association with other domains, such as SAND , PHD finger and Bromo , The HSR domain is predicted to be predominantly α-helical [, , ].
This entry includes a group of nuclear dot-associated proteins, including Sp110/Sp140/Sp140L from humans. They are proteins with a constituent of nuclear domains, also known as nuclear dots (NDs). Sequences similar to the Sp100 homodimerization/ND-targeting region occur in several other proteins and constitute a novel protein motif, termed HSR domain (for homogeneously-staining region) [].Sp110 is a leukocyte-specific component of the nuclear body []. It may function as a nuclear hormone receptor transcriptional coactivator that may play a role in inducing differentiation of myeloid cells []. It is also involved in resisting intracellular pathogens and functions as an important drug target for preventing intracellular pathogen diseases, such as tuberculosis, hepatic veno-occlusive disease, and intracellular cancers [, ]. Sp110 gene polymorphisms may be associated with susceptibility to tuberculosis in Chinese population []. The function of nuclear protein Sp140 is not known, though it contains several chromatin related modules such as plant homeodomain (PHD), bromodomain (BRD) and SAND domain, which suggests a role in chromatin-mediated regulation of gene expression []. It also harbours a nuclear localisation signal and a dimerisation domain (HSR or CARD domain). The PHD finger of Sp140 presents an atypical fold which does not bind to histone H3 tails but binds to peptidylprolyl isomerase Pin1. Pin1 catalyses the isomerisation of a phospho-Threonine-Proline bond in Sp140-PHD and thus may modulate Sp140 function [].Human Sp140 is an interferon inducible nuclear leukocyte-specific protein that may be involved in the pathogenesis of acute promyelocytic leukemia and viral infection []. It localises to LYSP100-associated nuclear dots and is also a component of the promyelocytic leukemia nuclear body (PML-NBs) [, ]. The Sp140 locus has been identified as a lymphocytic leukemia (CLL) risk locus [].This family also includes protein Sp140-like (SP140L) [].
The SAND domain (named after Sp100, AIRE-1, NucP41/75, DEAF-1) is a conserved ~80 residue region found in a number of nuclear proteins, many of which function in chromatin-dependent transcriptional control. These include proteins linked to various human diseases, such as the Sp100 (Speckled protein 100kDa) [], NUDR (Nuclear DEAF-1 related), GMEB (Glucocorticoid Modulatory Element Binding) proteins []and AIRE-1 (Autoimmune regulator 1) proteins.Proteins containing the SAND domain have a modular structure; the SAND domain can be associated with a number of other modules, including the bromodomain, the PHD finger and the MYND finger. Because no SAND domain has been found in yeast, it is thought that the SAND domain could be restricted to animal phyla. Many SAND domain-containing proteins, including NUDR, DEAF-1 (Deformed epidermal autoregulatory factor-1)and GMEB, have been shown to bind DNA sequences specifically. The SAND domain has been proposed to mediate the DNA binding activity of these proteins [, ].The resolution of the 3D structure of the SAND domain from Sp100b has revealed that it consists of a novel alpha/beta fold. The SAND domain adopts a compact fold consisting of a strongly twisted, five-stranded antiparallel β-sheet with four α-helices packing against one side of the β-sheet. The opposite side of the β-sheet is solvent exposed. The β-sheet and α-helical parts of the structure form two distinct regions.Multiple hydrophobic residues pack between these regions to form a structural core. A conserved KDWK sequence motif is found within the α-helical, positively charged surface patch. The DNA binding surface has been mapped to the α-helical region encompassing the KDWK motif [].
The SAND domain (named after Sp100, AIRE-1, NucP41/75, DEAF-1) is a conserved ~80 residue region found in a number of nuclear proteins, many of which function in chromatin-dependent transcriptional control. These include proteins linked to various human diseases, such as the Sp100 (Speckled protein 100kDa), NUDR (Nuclear DEAF-1 related), GMEB (Glucocorticoid Modulatory Element Binding) proteins and AIRE-1 (Autoimmune regulator 1) proteins.Proteins containing the SAND domain have a modular structure; the SAND domain can be associated with a number of other modules, including the bromodomain, the PHD finger and the MYND finger. Because no SAND domain has been found in yeast, it is thought that the SAND domain could be restricted to animal phyla. Many SAND domain-containing proteins, including NUDR, DEAF-1 (Deformed epidermal autoregulatory factor-1) and GMEB, have been shown to bind DNA sequences specifically. The SAND domain has been proposed to mediate the DNA binding activity of these proteins [, ]. Structurally, the SAND domain consists of a novel alpha/beta fold, which has a core of three short helices packed against a barrel-like β-sheet; it is structurally similar to the SH3-like fold.Other proteins display domains that are structurally similar to the SAND domain. One such example is the SMAD4-binding domain of the oncoprotein Ski, which is stabilised by a bound zinc atom, and resembles a SAND domain, in which the corresponding I loop is responsible for DNA binding. Ski is able to disrupt the formation of a functional complex between the Co- and R-SMADs, leading to the repression of TGF-beta, Activin and BMP responses, resulting in the repression of TGF-signalling [].
