6ujq

HHAT Wild Type Peptide KQWLVWLLL Presented by HLA-A206HHAT Wild Type Peptide KQWLVWLLL Presented by HLA-A206

Structural highlights

6ujq 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:	X-ray diffraction, Resolution 2.55Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HHAT_HUMAN Chondrodysplasia-disorder 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:31875564, PubMed:24784881). 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

T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope. The changes pre-organize the peptide into a conformation optimal for recognition by a neoepitope-specific T-cell receptor, allowing the receptor to bind the neoepitope with high affinity and deliver potent T-cell signals. Our results emphasize the importance of structural and physical changes relative to self in neoepitope immunogenicity. Considered broadly, these findings can help explain some of the difficulties in identifying immunogenic neoepitopes from sequence alone and provide guidance for developing novel, neoepitope-based personalized therapies.

Structural dissimilarity from self drives neoepitope escape from immune tolerance.,Devlin JR, Alonso JA, Ayres CM, Keller GLJ, Bobisse S, Vander Kooi CW, Coukos G, Gfeller D, Harari A, Baker BM Nat Chem Biol. 2020 Nov;16(11):1269-1276. doi: 10.1038/s41589-020-0610-1. Epub, 2020 Aug 17. PMID:32807968^[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:http://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:http://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:http://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:http://dx.doi.org/10.1016/j.celrep.2019.11.110
↑ Devlin JR, Alonso JA, Ayres CM, Keller GLJ, Bobisse S, Vander Kooi CW, Coukos G, Gfeller D, Harari A, Baker BM. Structural dissimilarity from self drives neoepitope escape from immune tolerance. Nat Chem Biol. 2020 Nov;16(11):1269-1276. PMID:32807968 doi:10.1038/s41589-020-0610-1

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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:http://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:http://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:http://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:http://dx.doi.org/10.1016/j.celrep.2019.11.110

[5] Devlin JR, Alonso JA, Ayres CM, Keller GLJ, Bobisse S, Vander Kooi CW, Coukos G, Gfeller D, Harari A, Baker BM. Structural dissimilarity from self drives neoepitope escape from immune tolerance. Nat Chem Biol. 2020 Nov;16(11):1269-1276. PMID:32807968 doi:10.1038/s41589-020-0610-1

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