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Effect of Homocysteine Thiolactone on Structure and Aggregation Propensity of Bovine Pancreatic Insulin

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Abstract

Homocysteine thiolactone (HCTL) is a cyclic thioester of homocysteine, showing high reactivity toward lysine residues of proteins. In the present study the structural properties and aggregation propensity of bovine pancreatic insulin were studied in the presences of increasing concentration of HCTL (0–500 μM), using different spectroscopic techniques. As shown in this study, HCTL induces gross structural alterations and subsequently aggregation of insulin in a dose dependent manner. Also induction of insulin aggregation by HCTL occurs in a sequential process, where native protein with alpha-helical abundant structure gradually transforms into partially folded conformations with the significant amount of beta-sheet. Since C-terminal B-chain of insulin plays a critical role in stability of this protein, the structural alteration/aggregation induced by HCTL can be consequence of homocysteinylation of the only Lysine residue (Lys29) on its B-chain. This study may have important implications regarding the effect of HCTL on structure of insulin particularly in the pathological states linked to hyperhomocysteinemia.

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Abbreviations

ANS:

1-anilino-8-naphthalene sulfonate

BLH:

Bleomycin hydrolase

CBS:

Cystathionine β-synthase

CD:

Circular dichroism

CDNN:

Context dependent neural networks

DLS:

Dynamic light scattering

HCTL:

Homocysteine thiolactone

Hcy:

Homocysteine

Lys:

Lysine

MetRS:

Methionyl-tRNA synthetase

MS:

Met synthase

MTHFR:

Methylene tetrahydrofolate reductase

PON1:

Paraoxonase 1

RH :

Hydrodynamic radius

UF:

Ultra filtration

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Acknowledgments

We would like to thank the research council of Shiraz University for the financial support (Grant number: 88-GR-SCST-112). Also the support of Iran National Science Foundation (INSF)/Grant number: 88001578 is gratefully acknowledged.

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Authors and Affiliations

  1. Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran

    Shima Jalili & Reza Yousefi

  2. Department of Chemistry, Shiraz University of Technology, Shiraz, Iran

    Mohammad-Mehdi Papari

  3. Institute of Biochemistry and Biophysics (IBB), The University of Tehran, Tehran, Iran

    Ali Akbar Moosavi-Movahedi

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  1. Shima Jalili
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  2. Reza Yousefi
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  3. Mohammad-Mehdi Papari
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  4. Ali Akbar Moosavi-Movahedi
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Correspondence to Reza Yousefi.

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Jalili, S., Yousefi, R., Papari, MM. et al. Effect of Homocysteine Thiolactone on Structure and Aggregation Propensity of Bovine Pancreatic Insulin. Protein J 30, 299–307 (2011). https://doi.org/10.1007/s10930-011-9333-1

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