The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis

The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis

^*Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; ^†Kemp Biotechnologies, Frederick, MD 21704; and ^‡Department of Internal Medicine and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75235

Edited by William N. Lipscomb, Harvard University, Cambridge, MA, and approved February 14, 2000 (received for review November 22, 1999)

Abstract

Mutations in palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme that removes fatty acyl groups from cysteine residues in modified proteins, cause the fatal inherited neurodegenerative disorder infantile neuronal ceroid lipofuscinosis. The accumulation of undigested substrates leads to the formation of neuronal storage bodies that are associated with the clinical symptoms. Less severe forms of PPT1 deficiency have been found recently that are caused by a distinct set of PPT1 mutations, some of which retain a small amount of thioesterase activity. We have determined the crystal structure of PPT1 with and without bound palmitate by using multiwavelength anomalous diffraction phasing. The structure reveals an α/β-hydrolase fold with a catalytic triad composed of Ser115-His289-Asp233 and provides insights into the structural basis for the phenotypes associated with PPT1 mutations.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: jcc12{at}cornell.edu.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 1EI9 and 1EH5).
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.080508097.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.080508097
Abbreviations:

PPT1,

palmitoyl protein thioesterase 1;

INCL,

infantile neuronal ceroid lipofuscinosis;

LINCL,

late infantile neuronal ceroid lipofuscinosis;

JNCL,

juvenile neuronal ceroid lipofuscinosis;

SeMet,

selenomethionine;

ACTE,

myristoyl-ACP thioesterase;

CHESS,

Cornell High Energy Synchrotron Source