A sterol-sensing domain (SSD) is a

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

which consists of 180 amino acids forming five

transmembrane segment A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...

s capable of binding

sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...

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-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and oth ...

(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 cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the prote ...

. The SSD is not required for the catalytic activity of HMGCR. * SREBP cleavage-activating protein (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-h ...

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 its s ...

. *

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 Protein patched homolog 1 is a protein that is the member of the patched family and in humans is encoded by the ''PTCH1'' gene. Function PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule ...

PTCH2 Patched 2 is a protein that in humans is encoded by the PTCH2 gene. Function This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway. Clin ...

), 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 Dispatched were a Swedish melodic death metal band from Södertälje (originally from the Gnesta Municipality) formed in 1992. History Dispatched was formed just before New Year's Eve, 1991 by Daniel Lundberg and Krister Andersson. Jonas Kimbr ...

(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 cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a bro ...

(SLOS). Mutations in NPC1 have been shown to cause

Niemann–Pick disease, type C Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimer's") is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present b ...

. Mutations in patched are associated with a variety of cancers (

basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

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 tumor are identified as rhabdomyoblasts. There are four subt ...

References

{{reflist Protein domains

Function

Disease

See also

References