Can misfolded proteins be beneficial? The HAMLET case.
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.
Pettersson-Kastberg
Jenny
J
Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, Lund, Sweden.
Aits
Sonja
S
Gustafsson
Lotta
L
Mossberg
Anki
A
Storm
Petter
P
Trulsson
Maria
M
Persson
Filip
F
Mok
K Hun
KH
Svanborg
Catharina
C
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D007768:Lactalbumin / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009829:Oleic Acids / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding
D000682:Amyloid; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; C506422:HAMLET complex, human; D009829:Oleic Acids; D011328:Prions; D007768:Lactalbumin; D002118:Calcium