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

John J. Bellizzi, Joanne Widom, Christopher Kemp, Jui Yun Lu, Amit K. Das, Sandra L. Hofmann, Jon Clardy

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4573-4578
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number9
DOIs
StatePublished - Apr 25 2000

ASJC Scopus subject areas

  • General

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