Restricted domain mobility in the Candida albicans Ess1 prolyl isomerase.

Abstract

Ess1 is a peptidyl prolyl cis/trans isomerase that is required for virulence of the pathogenic fungi Candida albicans and Cryptococcus neoformans. The enzyme isomerizes the phospho-Ser-Pro linkages in the C-terminal domain of RNA polymerase II. Its human homolog, Pin1, has been implicated in a wide range of human diseases, including cancer and Alzheimer's disease. Crystallographic and NMR studies have demonstrated that the sequence linking the catalytic isomerase domain and the substrate binding WW domain of Pin1 is unstructured and that the two domains are only loosely associated in the absence of the substrate. In contrast, the crystal structure of C. albicans Ess1 revealed a highly ordered linker that contains a three turn alpha-helix and extensive association between the two tightly juxtaposed domains. In part to address the concern that the marked differences in the domain interactions for the human and fungal structures might reflect crystal lattice effects, NMR chemical shift analysis and 15N relaxation measurements have been employed to confirm that the linker of the fungal protein is highly ordered in solution. With the exception of two loops within the active site of the isomerase domain, the local backbone geometry observed in the crystal structure appears to be well preserved throughout the protein chain. The marked differences in interdomain interactions and linker flexibility between the human and fungal enzymes provide a structural basis for therapeutic targeting of the fungal enzymes.

• Authors: Lynn McNaughton, Zhong Li, Patrick Van Roey, Steven D Hanes, David M LeMaster
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1804 Issue 7 Pg. 1537-41 (Jul 2010) ISSN: 0006-3002 [Print] Netherlands
• PMID: 20304107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• Fungal Proteins
• NIMA-Interacting Peptidylprolyl Isomerase
• Recombinant Proteins
• PIN1 protein, human
• Peptidylprolyl Isomerase

Topics

• Candida albicans (enzymology)
• Catalytic Domain
• Crystallography, X-Ray (methods)
• Fungal Proteins (chemistry)
• Humans
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Molecular Conformation
• NIMA-Interacting Peptidylprolyl Isomerase
• Peptidylprolyl Isomerase (chemistry, metabolism)
• Protein Conformation
• Protein Structure, Tertiary
• Recombinant Proteins (chemistry)
• Time Factors