Biology:SURF1

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Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene.[1][2] The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex), which is involved in the regulation of cytochrome c oxidase assembly.[3][4] Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase (complex IV) deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).[5][6]

Structure

SURF1 is located on the q arm of chromosome 9 in position 34.2 and has 9 exons.[5] The SURF1 gene produces a 33.3 kDa protein composed of 300 amino acids.[7][8] The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand.[5] SURF1 is a multi-pass protein that contains two transmembrane regions, one 19 amino acids in length from positions 61-79 and the other 17 amino acids in length from positions 274-290.[3][4]

Function

This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex.[5] SURF1 is a multi-pass membrane protein component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). The MITRAC complex regulates cytochrome c oxidase assembly by acting as a central assembly intermediate, receiving subunits imported to the inner mitochondrial membrane and regulating COX1 mRNA translation.[3][4][9]

Clinical significance

Mutations in SURF1 have been associated with mitochondrial complex IV (cytochrome c oxidase) deficiency with clinical manifestations of Leigh syndrome and Charcot-Marie-Tooth disease 4K (CMT4K).[3][4][10]

Mitochondrial complex IV deficiency

Mitochondrial complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. In patients presenting with pathogenic mutations resulting in dysfunctioning SURF1, cytochrome c oxidase activity is likely to be diminished in one or more types of tissues.[11][3][4]

Leigh syndrome

Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. There have been over 30 different mutations in SURF1 that have been associated with Leigh syndrome. These mutations, which comprise at least 10 missense or nonsense, 8 splice site, and 12 insertion or deletion mutations, are believed to be the result of dysfunctional SURF1 that results in Leigh syndrome and cytochrome c oxidase deficiency. The most common mutation is believed to be 312_321del 311_312insAT.[10][3][4]

Charcot-Marie-Tooth disease 4K (CMT4K)

Charcot-Marie-Tooth disease 4K (CMT4K) is an autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus, polyneuropathy, putaminal and periaqueductal lesions, and late-onset cerebellar ataxia. This disease, when associated with mutations in SURF1, has been found to be linked to cytochrome c oxidase deficiency. Variants associated with this CMT4K have included a homozygous splice site mutation, c.107-2A>G, a missense mutation, c.574C>T, and a deletion, c.799_800del.[6][3][4]

Interactions

SURF1 has been shown to have 11 binary protein-protein interactions including 8 co-complex interactions. SURF1 interacts with COA3 as part of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). PTGES3, SLC25A5, COX6C, COX14, COA1 have all also been found to interact with SURF1.[3][4][12]

References

  1. "The organization and conservation of the human Surfeit gene cluster and its localization telomeric to the c-abl and can proto-oncogenes at chromosome band 9q34.1". Human Molecular Genetics 2 (3): 237–40. March 1993. doi:10.1093/hmg/2.3.237. PMID 8499913. 
  2. "SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome". Nature Genetics 20 (4): 337–43. December 1998. doi:10.1038/3804. PMID 9843204. 
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "SURF1 - Surfeit locus protein 1 - Homo sapiens (Human) - SURF1 gene & protein" (in en). https://www.uniprot.org/uniprot/Q15526.  This article incorporates text available under the CC BY 4.0 license.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "UniProt: the universal protein knowledgebase". Nucleic Acids Research 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMID 27899622. 
  5. 5.0 5.1 5.2 5.3 "Entrez Gene: SURF1 surfeit 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6834.  This article incorporates text from this source, which is in the public domain.
  6. 6.0 6.1 "SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease". Neurology 81 (17): 1523–30. October 2013. doi:10.1212/WNL.0b013e3182a4a518. PMID 24027061. 
  7. Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". https://amino.heartproteome.org/web/protein/Q15526. 
  8. "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  9. "MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during Cytochrome c Oxidase Assembly". Cell Reports 12 (10): 1644–55. September 2015. doi:10.1016/j.celrep.2015.08.009. PMID 26321642. 
  10. 10.0 10.1 "Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency". Human Mutation 17 (5): 374–81. May 2001. doi:10.1002/humu.1112. PMID 11317352. 
  11. "Mitochondrial complex IV deficiency" (in en). https://www.uniprot.org/diseases/DI-01469. 
  12. IntAct. "https://www.ebi.ac.uk/intact/interactors/id:Q15526*" (in en). https://www.ebi.ac.uk/intact/interactors/id:Q15526*. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.