Can misfolded proteins be beneficial? The HAMLET case.

Jenny Pettersson, Sonja Aits, Lotta Gustafsson, Anki Mossberg, Petter Storm, Maria Trulsson, Filip Persson, K Hun Mok, Catharina Svanborg

Research output: Contribution to journalReview articlepeer-review

33 Citations (SciVal)

Abstract

By changing the three-dimensional structure, a protein can attain new functions, distinct from those of the native protein. Amyloid-forming proteins are one example, in which conformational change may lead to fibril formation and, in many cases, neurodegenerative disease. We have proposed that partial unfolding provides a mechanism to generate new and useful functional variants from a given polypeptide chain. Here we present HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) as an example where partial unfolding and the incorporation of cofactor create a complex with new, beneficial properties. Native alpha-lactalbumin functions as a substrate specifier in lactose synthesis, but when partially unfolded the protein binds oleic acid and forms the tumoricidal HAMLET complex. When the properties of HAMLET were first described they were surprising, as protein folding intermediates and especially amyloid-forming protein intermediates had been regarded as toxic conformations, but since then structural studies have supported functional diversity arising from a change in fold. The properties of HAMLET suggest a mechanism of structure-function variation, which might help the limited number of human protein genes to generate sufficient structural diversity to meet the diverse functional demands of complex organisms.
Original languageEnglish
Pages (from-to)162-176
JournalAnnals of Medicine
Volume41
DOIs
Publication statusPublished - 2009

Subject classification (UKÄ)

  • Medical and Health Sciences

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