Volume 96 Issue 3 | p. 9 | Concentrates
Issue Date: January 15, 2018

Palmitoyltransferase structures could aid inhibitor discovery

Enzymes add lipids to many proteins, including some associated with cancer
Department: Science & Technology
News Channels: Biological SCENE, Analytical SCENE
Keywords: Structural biology, palmitoyltransferase, cancer
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Human DHHC20 (yellow), in membrane of a cell organelle, has just transferred a palmitoyl group (white) to a protein (blue, right) and has another palmitoyl group ready for an incoming protein (blue, left). Gray spheres are Zn2+ ions.
Credit: Science
Cartoon image of human DHHC20 in a cell organelle membrane.
 
Human DHHC20 (yellow), in membrane of a cell organelle, has just transferred a palmitoyl group (white) to a protein (blue, right) and has another palmitoyl group ready for an incoming protein (blue, left). Gray spheres are Zn2+ ions.
Credit: Science

Palmitoyltransferases (PATs) are a bit of a mystery. These membrane-embedded enzymes add lipid groups of various lengths to more than 10% of human proteins, enhancing the proteins’ abilities to associate with cell and cell-organelle membranes. PATs also play important roles in cancer and other diseases. One called DHHC20 adds lipids to epidermal growth factor receptors like HER2, which is overexpressed in some breast cancer cells. But the PAT family was discovered only in 2002, and no one had succeeded in analyzing the structure of anything other than just a fragment of one of the enzymes. Now, by screening to find a PAT amenable to crystallization, mutating another to boost its tendency to crystallize, and laboriously optimizing the crystals that formed, Anirban Banerjee of the National Institute of Child Health & Human Development and coworkers have obtained key structural details on two PATs, DHHC20 from humans and DHHC15 from zebrafish (Science 2018, DOI: 10.1126/science.aao6326). In addition, the team’s characterization of PAT mutants enabled them to propose that PATs with larger active-site cavities catalyze the addition of longer lipids to protein substrates. Banerjee and coworkers hope to structurally analyze additional family members and screen for PAT inhibitors that might have anticancer or other therapeutic effects.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

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