SCP2-thiolase: Difference between revisions

Latest revision as of 08:44, 19 January 2020

Structure of the zebrafish SCP2-thiolase ^[1]

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Zebrafish SCP2-thiolase complex with CoA and octanoyl-CoA (PDB code 6hsp)

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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 ^[1]. 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.

↑ ^1.0 ^1.1 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

References

↑ Kiema TR, Thapa CJ, Laitaoja M, Schmitz W, Maksimainen MM, Fukao T, Rouvinen J, Janis J, Wierenga RK. The peroxisomal zebrafish SCP2-thiolase (type-1) is a weak transient dimer as revealed by crystal structures and native mass spectrometry. Biochem J. 2018 Dec 20. pii: BCJ20180788. doi: 10.1042/BCJ20180788. PMID:30573650 doi:https://dx.doi.org/10.1042/BCJ20180788

Proteopedia Page Contributors and Editors (what is this?)

Rik Wierenga, Michal Harel

[fingerprint-1] 1.0 ^1.1 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

[2] 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

[3] 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

[1] Kiema TR, Thapa CJ, Laitaoja M, Schmitz W, Maksimainen MM, Fukao T, Rouvinen J, Janis J, Wierenga RK. The peroxisomal zebrafish SCP2-thiolase (type-1) is a weak transient dimer as revealed by crystal structures and native mass spectrometry. Biochem J. 2018 Dec 20. pii: BCJ20180788. doi: 10.1042/BCJ20180788. PMID:30573650 doi:https://dx.doi.org/10.1042/BCJ20180788

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 ==Structure of the zebrafish SCP2-thiolase <ref>PMID:30573650</ref> ==
-<StructureSection load='6hsp' size='350' side='right' caption=' [[This is the asymmetric unit]] [[Resolution|1.7Å]] ' scene=''>
+<StructureSection load='6hsp' size='350' side='right' caption='Zebrafish SCP2-thiolase complex with CoA and octanoyl-CoA (PDB code [[6hsp]]) ' scene=''>
+==Introduction==
+The '''SCP2-thiolase''' is a member of the thiolase family of enzymes<ref name="fingerprint">PMID:24825023</ref>. 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 SCP2-thiolase is a member of the thiolase family of enzymes<ref>PMID:24825023</ref>. 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 <scene name='80/809821/6hsp-dimer/5'>symmetry copy</scene>.
+Each subunit can be divided in a <scene name='80/809821/6hsp-dimer-domain-coloring/1'>color coded</scene> N-terminal domain, a loop domain and a C-terminal domain.
+The active site is at the <scene name='80/809821/6hsp-dimer_active_site/2'>dimer interface</scene>.
-The active site is at the <scene name='80/809821/6hsp-dimer_active_site/1'>dimer interface</scene>
+Four loops provide critically important catalytic residues. These loops have characteristic sequence fingerprints <ref name="fingerprint"/>. These <scene name='80/809821/6hsp-dimer-catalytic-residues/3'>four loops</scene> are residues 87-89 (Nβ3-Nα3), 298-301 (Cβ2-Cα2), 347-349 (Cβ3-Cα3), 385-387 (Cβ4-Cβ5).
-The active site is shaped by the residues of <scene name='80/809821/6hsp-dimer-catalytic-residues/2'>four loops</scene>
-== Function ==
-Here '''something''' about ''function'' <ref>pmid 25203508</ref>
-== Disease ==
-== Relevance ==
+== Function and Disease==
+The SCP2 thiolase functions in the bile acid synthesis pathway <ref>pmid 9325339</ref>. 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. <ref>pmid 16685654</ref>
 == Structural highlights ==
+When the A and B monomers are compared the structural differences can best be seen in this <scene name='80/809821/Morph/10'>morph</scene>.
-When the A and B monomers are compared the structural differences can best be seen in this <scene name='80/809821/morph-movie/1'>morph</scene>.
-This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 </StructureSection>
 == References ==
 <references/>

SCP2-thiolase: Difference between revisions

Latest revision as of 08:44, 19 January 2020

Structure of the zebrafish SCP2-thiolase ^[1]

Introduction

Function and Disease

Structural highlights

References

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SCP2-thiolase: Difference between revisions

Latest revision as of 08:44, 19 January 2020

Structure of the zebrafish SCP2-thiolase [1]

Introduction

Function and Disease

Structural highlights

References

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Search

Structure of the zebrafish SCP2-thiolase ^[1]