Journal
ANNALS OF MEDICINE
Volume 41, Issue 3, Pages 162-176Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/07853890802502614
Keywords
Amyloid; cancer; cell death; HAMLET complex; lactalbumin; oleic acid; prions; protein folding
Categories
Funding
- Sharon D. Lund foundation
- American Cancer Society
- Swedish Cancer Society
- Swedish Pediatric Cancer Foundation
- Medical Faculty (Lund University)
- S-derberg Foundation
- Segerfalk Foundation
- French Medical Research Foundation (FRM, Paris)
- Anna-Lisa and Sven-Erik Lundgren Foundation for Medical Research
- Knut Alice Wallenberg Foundation
- Lund City Jubileumsfond
- John and Augusta Persson Foundation
- Maggie Stephens Foundation
- Gunnar Nilsson Cancer Foundation
- Inga-Britt och Arne Lundberg foundation
- HJ Forssman Foundation for Medical Research
- Royal Physiographic Society
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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 -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.
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