Can misfolded proteins be beneficial? The HAMLET case.
(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:
https://lup.lub.lu.se/record/1271814
- author
- 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
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Annals of Medicine
- volume
- 41
- pages
- 162 - 176
- publisher
- Taylor & Francis
- external identifiers
-
- wos:000264271000001
- pmid:18985467
- scopus:67650379261
- pmid:18985467
- ISSN
- 1365-2060
- DOI
- 10.1080/07853890802502614
- project
- HAMLET- In vivo effects and mechanisms of tumor cells death
- 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
- 2016-04-01 12:02:14
- date last changed
- 2024-05-07 02:24:33
@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 = {{Taylor & Francis}}, series = {{Annals of Medicine}}, title = {{Can misfolded proteins be beneficial? The HAMLET case.}}, url = {{http://dx.doi.org/10.1080/07853890802502614}}, doi = {{10.1080/07853890802502614}}, volume = {{41}}, year = {{2009}}, }