7k0j | pdb_00007k0j

Human serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa protomer

Structural highlights

7k0j is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:	PLP, POV
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SPTC1_HUMAN Hereditary sensory and autonomic neuropathy type 1;Juvenile amyotrophic lateral sclerosis. The disease is caused by variants affecting the gene represented in this entry. Variants associated with ALS27 tend to disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated SPT activity and elevated levels of canonical SPT products.^[1] The disease is caused by variants affecting the gene represented in this entry. Variants associated with HSAN1A tend to increase serine palmitoyltransferase (SPT) usage of alanine or glycine rather than serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids cannot be efficiently degraded by the cell machinery and cause cell toxicity.^[2]

Function

SPTC1_HUMAN Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core (PubMed:19416851, PubMed:33558762, PubMed:36170811). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA (PubMed:19416851, PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (PubMed:19416851, PubMed:19648650, PubMed:33558761, PubMed:33558762). Required for adipocyte cell viability and metabolic homeostasis (By similarity).[UniProtKB:O35704]^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

Sphingolipids are essential lipids in eukaryotic membranes. In humans, the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and ORMDL3). However, the assembly, substrate processing and regulation of the complex are unclear. Here, we present 8 cryo-electron microscopy structures of the human serine palmitoyltransferase holocomplex in various functional states at resolutions of 2.6-3.4 A. The structures reveal not only how catalytic components recognize the substrate, but also how regulatory components modulate the substrate-binding tunnel to control enzyme activity: ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity. ORMDL3 blocks the tunnel and competes with substrate binding through its amino terminus. These findings provide mechanistic insights into sphingolipid biogenesis governed by the serine palmitoyltransferase complex.

, PMID:33558761^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, Fiorillo C, Ly CV, Töpf A, Brady L, Specht S, Zidell A, Pedro H, Mittelmann E, Thomas FP, Chao KR, Konersman CG, Cho MT, Brandt T, Straub V, Connolly AM, Schara U, Roos A, Tarnopolsky M, Höke A, Brown RH, Lee CH, Hornemann T, Dunn TM, Bönnemann CG. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat Med. 2021 Jul;27(7):1197-1204. PMID:34059824 doi:10.1038/s41591-021-01346-1
↑ Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, Fiorillo C, Ly CV, Töpf A, Brady L, Specht S, Zidell A, Pedro H, Mittelmann E, Thomas FP, Chao KR, Konersman CG, Cho MT, Brandt T, Straub V, Connolly AM, Schara U, Roos A, Tarnopolsky M, Höke A, Brown RH, Lee CH, Hornemann T, Dunn TM, Bönnemann CG. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat Med. 2021 Jul;27(7):1197-1204. PMID:34059824 doi:10.1038/s41591-021-01346-1
↑ Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM, Dunn TM. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8186-91. PMID:19416851 doi:10.1073/pnas.0811269106
↑ Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009 Sep 25;284(39):26322-30. PMID:19648650 doi:10.1074/jbc.M109.023192
↑ Wang Y, Niu Y, Zhang Z, Gable K, Gupta SD, Somashekarappa N, Han G, Zhao H, Myasnikov AG, Kalathur RC, Dunn TM, Lee CH. Structural insights into the regulation of human serine palmitoyltransferase complexes. Nat Struct Mol Biol. 2021 Mar;28(3):240-248. PMID:33558761 doi:10.1038/s41594-020-00551-9
↑ Li S, Xie T, Liu P, Wang L, Gong X. Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex. Nat Struct Mol Biol. 2021 Mar;28(3):249-257. PMID:33558762 doi:10.1038/s41594-020-00553-7
↑ Spears ME, Lee N, Hwang S, Park SJ, Carlisle AE, Li R, Doshi MB, Armando AM, Gao J, Simin K, Zhu LJ, Greer PL, Quehenberger O, Torres EM, Kim D. De novo sphingolipid biosynthesis necessitates detoxification in cancer cells. Cell Rep. 2022 Sep 27;40(13):111415. PMID:36170811 doi:10.1016/j.celrep.2022.111415
↑ Wang Y, Niu Y, Zhang Z, Gable K, Gupta SD, Somashekarappa N, Han G, Zhao H, Myasnikov AG, Kalathur RC, Dunn TM, Lee CH. Structural insights into the regulation of human serine palmitoyltransferase complexes. Nat Struct Mol Biol. 2021 Mar;28(3):240-248. PMID:33558761 doi:10.1038/s41594-020-00551-9

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OCA

[1] Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, Fiorillo C, Ly CV, Töpf A, Brady L, Specht S, Zidell A, Pedro H, Mittelmann E, Thomas FP, Chao KR, Konersman CG, Cho MT, Brandt T, Straub V, Connolly AM, Schara U, Roos A, Tarnopolsky M, Höke A, Brown RH, Lee CH, Hornemann T, Dunn TM, Bönnemann CG. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat Med. 2021 Jul;27(7):1197-1204. PMID:34059824 doi:10.1038/s41591-021-01346-1

[2] Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, Fiorillo C, Ly CV, Töpf A, Brady L, Specht S, Zidell A, Pedro H, Mittelmann E, Thomas FP, Chao KR, Konersman CG, Cho MT, Brandt T, Straub V, Connolly AM, Schara U, Roos A, Tarnopolsky M, Höke A, Brown RH, Lee CH, Hornemann T, Dunn TM, Bönnemann CG. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat Med. 2021 Jul;27(7):1197-1204. PMID:34059824 doi:10.1038/s41591-021-01346-1

[3] Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM, Dunn TM. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8186-91. PMID:19416851 doi:10.1073/pnas.0811269106

[4] Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009 Sep 25;284(39):26322-30. PMID:19648650 doi:10.1074/jbc.M109.023192

[5] Wang Y, Niu Y, Zhang Z, Gable K, Gupta SD, Somashekarappa N, Han G, Zhao H, Myasnikov AG, Kalathur RC, Dunn TM, Lee CH. Structural insights into the regulation of human serine palmitoyltransferase complexes. Nat Struct Mol Biol. 2021 Mar;28(3):240-248. PMID:33558761 doi:10.1038/s41594-020-00551-9

[6] Li S, Xie T, Liu P, Wang L, Gong X. Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex. Nat Struct Mol Biol. 2021 Mar;28(3):249-257. PMID:33558762 doi:10.1038/s41594-020-00553-7

[7] Spears ME, Lee N, Hwang S, Park SJ, Carlisle AE, Li R, Doshi MB, Armando AM, Gao J, Simin K, Zhu LJ, Greer PL, Quehenberger O, Torres EM, Kim D. De novo sphingolipid biosynthesis necessitates detoxification in cancer cells. Cell Rep. 2022 Sep 27;40(13):111415. PMID:36170811 doi:10.1016/j.celrep.2022.111415

[8] Wang Y, Niu Y, Zhang Z, Gable K, Gupta SD, Somashekarappa N, Han G, Zhao H, Myasnikov AG, Kalathur RC, Dunn TM, Lee CH. Structural insights into the regulation of human serine palmitoyltransferase complexes. Nat Struct Mol Biol. 2021 Mar;28(3):240-248. PMID:33558761 doi:10.1038/s41594-020-00551-9

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7k0j | pdb_00007k0j

Human serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa protomer

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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