DDHD2
Domain
SAM and DDHD domains together are required for phospholipid binding.
Function
Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system (PubMed:29278326, PubMed:37832604). It cooperates with PNPLA2/ATGL in neuronal TAG catabolism and hydrolyzes sn-1,3 DAG downstream of PNPLA2/ATGL (By similarity). In vitro, it also acts as a phospholipase that hydrolyzes preferentially phosphatidic acids, including 1,2-dioleoyl-sn-phosphatidic acid, phosphatidylcholine and phosphatidylethanolamine. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be involved in the maintenance of the endoplasmic reticulum and/or Golgi structures. May regulate the transport between Golgi apparatus and plasma membrane.
Involvement in disease
Spastic paraplegia 54, autosomal recessive
SPG54
A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG54 patients have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions, and an abnormal lipid peak due to accumulation of neutral lipids in certain brain regions.
None
The disease is caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the PA-PLA1 family.
Tissue Specificity
Widely expressed (at protein level).
Cellular localization
- Cytoplasm
- Cytosol
- Endoplasmic reticulum-Golgi intermediate compartment
- Golgi apparatus
- cis-Golgi network
- Cycles between the Golgi apparatus and the cytosol. DDHD2 recruitment to the Golgi/endoplasmic reticulum-Golgi intermediate compartment (ERGIC) is regulated by the levels of phosphoinositides, including PI(4)P.
Alternative names
KIAA0725, SAMWD1, DDHD2, Triacylglycerol hydrolase DDHD2, TAG hydrolase, DDHD domain-containing protein 2, KIAA0725p, Phospholipase DDHD2, Triglyceride hydrolase DDHD2, Triglyceride lipase