Introduction
The SCP2-thiolase is a member of the thiolase family of enzymes[1]. It has low sequence identity with any of the other thiolases. Like many other thiolases it is a dimer in solution. In the 6HSP crystal structure there are two monomers per asymmetric unit. One monomer forms the classical dimer with a two-fold related symmetry mate. The other monomer has a different packing and it is not forming the classical dimer: its structure is the structure of the monomer. There are large structural differences between these two monomers. The comparison of the structures of the "dimerised" monomer and the single monomer visualises the structural changes that happen when the single monomer dimerises to form the mature dimer.
The A-monomer is the single monomer, and the B-monomer is forming a dimer with its two-fold crystallographically related symmetry copy.
Each subunit can be divided in a color coded N-terminal domain, a loop domain and a C-terminal domain.
The active site is at the dimer interface.
Four loops provide critically important catalytic residues. These loops have characteristic sequence fingerprints. These four loops are residues 87-89 (Nβ3-Nα3), 298-301 (Cβ2-Cα2), 347-349 (Cβ3-Cα3), 385-387 (Cβ4-Cβ5).
Function and Disease
The SCP2 thiolase functions in the bile acid synthesis pathway [2]. SCP2-thiolase is synthesised as a larger protein, having the thiolase part and at the C-terminal end there is an extra domainn, the SCP2-domain. This domain has the sequence SKL at its C-terminus, which functions as the peroxisomal targetting sequence. In the peroxisome the SCP2-domain is proteolytically cleaved off, and the SCP2-thiolase chain is found to be present in the peroxisome, as described by Wanders and coworkers, who also described the deficiency symptoms in case the SCP2-thiolase is not properly expressed. [3]
Structural highlights
When the A and B monomers are compared the structural differences can best be seen in this morph.
- ↑ Anbazhagan P, Harijan RK, Kiema TR, Janardan N, Murthy MR, Michels PA, Juffer AH, Wierenga RK. Phylogenetic relationships and classification of thiolases and thiolase-like proteins of Mycobacterium tuberculosis and Mycobacterium smegmatis. Tuberculosis (Edinb). 2014 Jul;94(4):405-12. doi: 10.1016/j.tube.2014.03.003., Epub 2014 Apr 4. PMID:24825023 doi:https://dx.doi.org/10.1016/j.tube.2014.03.003
- ↑ Antonenkov VD, Van Veldhoven PP, Waelkens E, Mannaerts GP. Substrate specificities of 3-oxoacyl-CoA thiolase A and sterol carrier protein 2/3-oxoacyl-CoA thiolase purified from normal rat liver peroxisomes. Sterol carrier protein 2/3-oxoacyl-CoA thiolase is involved in the metabolism of 2-methyl-branched fatty acids and bile acid intermediates. J Biol Chem. 1997 Oct 10;272(41):26023-31. PMID:9325339
- ↑ Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, Reith W, Haas D, Wanders RJ, Duran M, Marziniak M. Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet. 2006 Jun;78(6):1046-52. Epub 2006 Mar 29. PMID:16685654 doi:10.1086/503921
