2.A.50.1.4 SKI1, HHAT or MART2 (The Sonic Hedgehog) of 493 aas and 11 - 13 TMSs. Before they can function as signaling molecules, Hedgehog precursor
proteins must undergo amino-terminal palmitoylation by Hedgehog
acyltransferase (HHAT). Jiang et al. 2021 presented cryo-EM 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 revealed 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 (Jiang et al. 2021). The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by HHAT. Coupland et al. 2021 presented a high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. The analysis provided a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery (Coupland et al. 2021).
|
Accession Number: | Q5VTY9 |
Protein Name: | Protein-cysteine N-palmitoyltransferase HHAT |
Length: | 493 |
Molecular Weight: | 57313.00 |
Species: | Homo sapiens (Human) [9606] |
Number of TMSs: | 11 |
Location1 / Topology2 / Orientation3: |
Endoplasmic reticulum membrane1 / Multi-pass membrane protein2 |
Substrate |
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1: MLPRWELALY LLASLGFHFY SFYEVYKVSR EHEEELDQEF ELETDTLFGG LKKDATDFEW
61: SFWMEWGKQW LVWLLLGHMV VSQMATLLAR KHRPWILMLY GMWACWCVLG TPGVAMVLLH
121: TTISFCVAQF RSQLLTWLCS LLLLSTLRLQ GVEEVKRRWY KTENEYYLLQ FTLTVRCLYY
181: TSFSLELCWQ QLPAASTSYS FPWMLAYVFY YPVLHNGPIL SFSEFIKQMQ QQEHDSLKAS
241: LCVLALGLGR LLCWWWLAEL MAHLMYMHAI YSSIPLLETV SCWTLGGLAL AQVLFFYVKY
301: LVLFGVPALL MRLDGLTPPA LPRCVSTMFS FTGMWRYFDV GLHNFLIRYV YIPVGGSQHG
361: LLGTLFSTAM TFAFVSYWHG GYDYLWCWAA LNWLGVTVEN GVRRLVETPC IQDSLARYFS
421: PQARRRFHAA LASCSTSMLI LSNLVFLGGN EVGKTYWNRI FIQGWPWVTL SVLGFLYCYS
481: HVGIAWAQTY ATD