期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 6, 页码 3293-3307出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.614578
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资金
- Pancreatic Cancer Research Fund
- Cancer Research UK
- NHLI Foundation
- Imperial College London Institute of Chemical Biology EPSRC Centre for Doctoral Training [EP/F500416/1]
- EPSRC [EP/J021199/1] Funding Source: UKRI
- MRC [G0400710] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [978583] Funding Source: researchfish
- Cancer Research UK [16402] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/J021199/1] Funding Source: researchfish
- Medical Research Council [G0400710] Funding Source: researchfish
Hedgehog proteins are secreted morphogens that play critical roles in development and disease. During maturation of the proteins through the secretory pathway, they are modified by the addition of N-terminal palmitic acid and C-terminal cholesterol moieties, both of which are critical for their correct function and localization. Hedgehog acyltransferase(HHAT) is the enzyme in the endoplasmic reticulum that palmitoylates Hedgehog proteins, is a member of a small subfamily of membrane-bound O-acyltransferase proteins that acylate secreted proteins, and is an important drug target in cancer. However, little is known about HHAT structure and mode of function. We show that HHAT is comprised of ten transmembrane domains and two reentrant loops with the critical His and Asp residues on opposite sides of the endoplasmic reticulum membrane. We further show that HHAT is palmitoylated on multiple cytosolic cysteines that maintain protein structure within the membrane. Finally, we provide evidence that mutation of the conserved His residue in the hypothesized catalytic domain results in a complete loss ofHHATpalmitoylation, providing novel insights into how the protein may function in vivo.
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