7mhy | pdb_00007mhy

Human Hedgehog acyltransferase (HHAT) in complex with palmitoyl-CoA and two Fab antibody fragments

Structural highlights

7mhy is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.7Å
Ligands:	AJP, HEM, PKZ
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HHAT_HUMAN Chondrodysplasia-difference of sex development syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

HHAT_HUMAN Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling (PubMed:18534984, PubMed:24784881, PubMed:31875564). It also catalyzes N-terminal palmitoylation of DHH (PubMed:24784881). Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs (PubMed:31875564). It is an essential factor for proper embryonic development and testicular organogenesis (PubMed:24784881).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Hedgehog proteins govern crucial developmental steps in animals and drive certain human cancers. Before they can function as signaling molecules, Hedgehog precursor proteins must undergo amino-terminal palmitoylation by Hedgehog acyltransferase (HHAT). We present cryo-electron microscopy structures of human HHAT in complex with its palmitoyl-coenzyme A substrate and of a product complex with a palmitoylated Hedgehog peptide at resolutions of 2.7 and 3.2 angstroms, respectively. The structures reveal how HHAT overcomes the challenges of bringing together substrates that have different physiochemical properties from opposite sides of the endoplasmic reticulum membrane within a membrane-embedded active site for catalysis. These principles are relevant to related enzymes that catalyze the acylation of Wnt and of the appetite-stimulating hormone ghrelin. The structural and mechanistic insights may advance the development of inhibitors for cancer.

Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.,Jiang Y, Benz TL, Long SB Science. 2021 Jun 11;372(6547):1215-1219. doi: 10.1126/science.abg4998. PMID:34112694^[5]

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

References

↑ Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science. 2001 Sep 14;293(5537):2080-4. doi: 10.1126/science.1064437. Epub 2001, Aug 2. PMID:11486055 doi:https://dx.doi.org/10.1126/science.1064437
↑ Buglino JA, Resh MD. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem. 2008 Aug 8;283(32):22076-88. doi: 10.1074/jbc.M803901200. Epub 2008 , Jun 4. PMID:18534984 doi:https://dx.doi.org/10.1074/jbc.M803901200
↑ Callier P, Calvel P, Matevossian A, Makrythanasis P, Bernard P, Kurosaka H, Vannier A, Thauvin-Robinet C, Borel C, Mazaud-Guittot S, Rolland A, Desdoits-Lethimonier C, Guipponi M, Zimmermann C, Stevant I, Kuhne F, Conne B, Santoni F, Lambert S, Huet F, Mugneret F, Jaruzelska J, Faivre L, Wilhelm D, Jegou B, Trainor PA, Resh MD, Antonarakis SE, Nef S. Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genet. 2014 May 1;10(5):e1004340. doi: 10.1371/journal.pgen.1004340., eCollection 2014 May. PMID:24784881 doi:https://dx.doi.org/10.1371/journal.pgen.1004340
↑ Asciolla JJ, Resh MD. Hedgehog Acyltransferase Promotes Uptake of Palmitoyl-CoA across the Endoplasmic Reticulum Membrane. Cell Rep. 2019 Dec 24;29(13):4608-4619.e4. doi: 10.1016/j.celrep.2019.11.110. PMID:31875564 doi:https://dx.doi.org/10.1016/j.celrep.2019.11.110
↑ Jiang Y, Benz TL, Long SB. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Science. 2021 Jun 11;372(6547):1215-1219. PMID:34112694 doi:10.1126/science.abg4998

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science. 2001 Sep 14;293(5537):2080-4. doi: 10.1126/science.1064437. Epub 2001, Aug 2. PMID:11486055 doi:https://dx.doi.org/10.1126/science.1064437

[2] Buglino JA, Resh MD. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem. 2008 Aug 8;283(32):22076-88. doi: 10.1074/jbc.M803901200. Epub 2008 , Jun 4. PMID:18534984 doi:https://dx.doi.org/10.1074/jbc.M803901200

[3] Callier P, Calvel P, Matevossian A, Makrythanasis P, Bernard P, Kurosaka H, Vannier A, Thauvin-Robinet C, Borel C, Mazaud-Guittot S, Rolland A, Desdoits-Lethimonier C, Guipponi M, Zimmermann C, Stevant I, Kuhne F, Conne B, Santoni F, Lambert S, Huet F, Mugneret F, Jaruzelska J, Faivre L, Wilhelm D, Jegou B, Trainor PA, Resh MD, Antonarakis SE, Nef S. Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genet. 2014 May 1;10(5):e1004340. doi: 10.1371/journal.pgen.1004340., eCollection 2014 May. PMID:24784881 doi:https://dx.doi.org/10.1371/journal.pgen.1004340

[4] Asciolla JJ, Resh MD. Hedgehog Acyltransferase Promotes Uptake of Palmitoyl-CoA across the Endoplasmic Reticulum Membrane. Cell Rep. 2019 Dec 24;29(13):4608-4619.e4. doi: 10.1016/j.celrep.2019.11.110. PMID:31875564 doi:https://dx.doi.org/10.1016/j.celrep.2019.11.110

[5] Jiang Y, Benz TL, Long SB. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Science. 2021 Jun 11;372(6547):1215-1219. PMID:34112694 doi:10.1126/science.abg4998

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7mhy | pdb_00007mhy

Human Hedgehog acyltransferase (HHAT) in complex with palmitoyl-CoA and two Fab antibody fragments

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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