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HIV protease substrate conformation: modulation by cyclophilin A

M A McCornack¹, L T Kakalis, C Caserta

¹Department of Biochemistry, University of Minnesota, Minneapolis 55455-0347, USA.

|September 26, 1997

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Cyclophilin A (CyPA) acts as a peptidyl-prolyl isomerase, accelerating peptide bond changes. This study shows CyPA facilitates the cis conformation of a specific HIV-1 protease cleavage site peptide, a process inhibited by cyclosporin A.

Area of Science:

Biochemistry
Molecular Biology
Structural Biology

Background:

Cyclophilin A (CyPA) is a cytosolic enzyme catalyzing peptidyl-prolyl trans-cis isomerization.
The HIV-1 protease cleaves the gag polyprotein at specific Xxx-Pro peptide bonds, crucial for viral replication.

Purpose of the Study:

To investigate if CyPA acts on a model peptide representing an HIV-1 protease cleavage site.
To characterize the kinetics and conformational changes of the peptide bond isomerization mediated by CyPA.

Main Methods:

One- and two-dimensional 1H-NMR spectroscopy were employed.
Saturation transfer and Nuclear Overhauser Effect (NOE) experiments were utilized to study interconversion rates.

Main Results:

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The heptapeptide Ser-Gln-Asn-Tyr-Pro-Ile-Val was identified as a substrate for CyPA.
A slow trans-cis isomerization of the Tyr-Pro peptide bond was observed, with ~30% in the cis conformation.
CyPA significantly enhanced the rate of this trans-cis interconversion.
Cyclosporin A (CsA) was found to inhibit this CyPA-mediated process.
An interconversion rate of 2.5 s(-1) at 25 degrees C was measured at a 40:1 substrate:CyPA ratio.

Conclusions:

CyPA directly interacts with and accelerates the isomerization of a key peptide bond within an HIV-1 protease cleavage site mimic.
This enzymatic activity is modulated by cyclosporin A, suggesting potential therapeutic implications.
The findings provide insights into the role of protein isomerases in viral polyprotein processing.