A sterol-sensing domain (SSD) is a

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

which consists of 180 amino acids forming five transmembrane segments capable of binding

sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...

groups. This type of domain is present in proteins involved in cholesterol metabolism and signalling.

Function

Sterol-sensing domains are present in various proteins involved in key aspects of cholesterol homeostasis and signalling. Multiple sequence alignments using Clustal W have shown that these proteins can be grouped in seven different families according to their SSDs. The following SSD-containing proteins represent each family: *

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-limiting enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other ...

(HMGCR), involved in the biosynthesis of cholesterol. This was the first protein with an SSD to be discovered. Upon binding to cholesterol, this protein undergoes

endoplasmic-reticulum-associated protein degradation Endoplasmic-reticulum-associated protein degradation (ERAD) designates a Cell (biology), cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, c ...

. The SSD is not required for the catalytic activity of HMGCR. *

SREBP cleavage-activating protein Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP, is a protein that in humans is encoded by the ''SCAP'' gene. SCAP contains a sterol-sensing domain (SSD) and seven ...

(SCAP), which regulates transcription of genes with sterol response elements by proteolytically activating

sterol regulatory element-binding protein Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes ''SREBF1'' and ''SREBF2''. SREBPs belong to the basic-hel ...

s (SREBPs). This was the second SSD-containing protein to be discovered. * 7-dehydrocholesterol reductase (7DHCR), involved in the last step of cholesterol biosynthesis. * Niemann-Pick type C1 (NPC1), involved in intracellular cholesterol transport. ** Niemann-Pick type C1-like 1 (NPC1L1), a regulator of cholesterol absorption in

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase i ...

. *

Patched Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segme ...

( PTCH1, PTCH2), involved in the

hedgehog signaling pathway The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...

and also cytokinesis. Its SSD binds the cholesterol moiety of hedgehog, and it is essential for its activity. * Dispatched (DISP1, DISP2, DISP3), also involved in hedgehog signaling. DISP is required for the secretion of hedgehog. * Patched-related protein (PTR), structurally similar to patched. Its functions are not fully understood.

Disease

Mutations in 7DHCR are linked to

Smith–Lemli–Opitz syndrome Smith–Lemli–Opitz syndrome is an inborn error of metabolism, inborn error of cholesterol synthesis. It is an autosome, autosomal recessive (genetics), recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrochole ...

(SLOS). Mutations in NPC1 have been shown to cause Niemann–Pick disease, type C. Mutations in patched are associated with a variety of cancers (

basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma, or rodent ulcer, is the most common type of skin cancer. It often appears as a painless, raised area of skin, which may be shiny with Telangiectasia, small blood vessels ru ...

, medulloblastoma,

rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the neoplasm, tumor are identified as rhabdomyoblasts. The four ...

References

{{reflist Protein domains

Function

Disease

See also

References