Advanced

Can misfolded proteins be beneficial? The HAMLET case.

Pettersson, Jenny LU ; Aits, Sonja LU ; Gustafsson, Lotta LU ; Mossberg, Anki LU ; Storm, Petter LU ; Trulsson, Maria LU ; Persson, Filip; Hun Mok, K and Svanborg, Catharina LU (2009) In Annals of Medicine 41. p.162-176
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Annals of Medicine
volume
41
pages
162 - 176
publisher
Informa Healthcare
external identifiers
  • wos:000264271000001
  • pmid:18985467
  • scopus:67650379261
ISSN
1365-2060
DOI
10.1080/07853890802502614
language
English
LU publication?
yes
id
a3328c5d-2929-40f8-9a74-6faa93175aa7 (old id 1271814)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18985467?dopt=Abstract
date added to LUP
2008-12-01 15:10:25
date last changed
2017-11-12 03:24:39
@article{a3328c5d-2929-40f8-9a74-6faa93175aa7,
  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.},
  author       = {Pettersson, Jenny and Aits, Sonja and Gustafsson, Lotta and Mossberg, Anki and Storm, Petter and Trulsson, Maria and Persson, Filip and Hun Mok, K and Svanborg, Catharina},
  issn         = {1365-2060},
  language     = {eng},
  pages        = {162--176},
  publisher    = {Informa Healthcare},
  series       = {Annals of Medicine},
  title        = {Can misfolded proteins be beneficial? The HAMLET case.},
  url          = {http://dx.doi.org/10.1080/07853890802502614},
  volume       = {41},
  year         = {2009},
}