- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- BIRS Workshop Lecture Videos /
- Novel knotted structure
Open Collections
BIRS Workshop Lecture Videos
BIRS Workshop Lecture Videos
Novel knotted structure Haglund, Ellinor
Description
We discovered hidden complexity in the cysteine-knotted topology of the cytokine leptin characterized by a covalent loop (a so-called zero knot) where part of a terminus is slipknotted through the zero knot. We call this motif a Cysteine Knotted Helical Bundle (CKHB). Up to date, there have been no reports of four-helix bundles with similar threaded topology. We explored the question: Do other proteins contain similar CKHBs? We discovered 11 proteins with similar threaded topology. However, leptin is the only motif with a C-terminal zero knot whereas all other structures have an N-terminal zero knot.Structure-based models were used to in investigate the folding/threading mechanism for six four-helix bundles: four with a threaded topology and two unknotted cytokine homologs. We found that the order of events in folding of the four-helix-bundle is conserved and that the nucleation site for folding is the C-terminal helix. Leptin uses a variation of the same mechanism, but in a unique reversed order in which large structural components of the protein start out as part of the zero knot. This contrasts with the other four-helix bundles, which use large structural components as a scaffold for loop formation. Remarkably, leptin slipknots large structure parts through the C-terminal zero knot while the other CKHBs threads its C-terminal through the N- terminal zero knot like a thread through a needle (a so-called plugging mechanism). Conclusively, since four-helix bundles have similar functional and folding landscape it is important to point out that CHKBs with an N-terminal loop pin down the N-terminal helix (helix A), while leptin has the opposite zero knot, thus keeping the N-terminal dynamic. Crystal structures and modelling of receptor complexes reveals one conserved interface (helix A interacting with the receptor) within the cytokines. This suggests a more dynamic assembly process between leptin and its receptor where the malleability of helix A could affect binding affinity and signaling.
Item Metadata
Title |
Novel knotted structure
|
Creator | |
Publisher |
Banff International Research Station for Mathematical Innovation and Discovery
|
Date Issued |
2013-11-18
|
Description |
We discovered hidden complexity in the cysteine-knotted topology of the cytokine leptin characterized by a covalent loop (a so-called zero knot) where part of a terminus is slipknotted through the zero knot. We call this motif a Cysteine Knotted Helical Bundle (CKHB). Up to date, there have been no reports of four-helix bundles with similar threaded topology. We explored the question: Do other proteins contain similar CKHBs? We discovered 11 proteins with similar threaded topology. However, leptin is the only motif with a C-terminal zero knot whereas all other structures have an N-terminal zero knot.Structure-based models were used to in investigate the folding/threading mechanism for six four-helix bundles: four with a threaded topology and two unknotted cytokine homologs. We found that the order of events in folding of the four-helix-bundle is conserved and that the nucleation site for folding is the C-terminal helix. Leptin uses a variation of the same mechanism, but in a unique reversed order in which large structural components of the protein start out as part of the zero knot. This contrasts with the other four-helix bundles, which use large structural components as a scaffold for loop formation. Remarkably, leptin slipknots large structure parts through the C-terminal zero knot while the other CKHBs threads its C-terminal through the N- terminal zero knot like a thread through a needle (a so-called plugging mechanism). Conclusively, since four-helix bundles have similar functional and folding landscape it is important to point out that CHKBs with an N-terminal loop pin down the N-terminal helix (helix A), while leptin has the opposite zero knot, thus keeping the N-terminal dynamic. Crystal structures and modelling of receptor complexes reveals one conserved
interface (helix A interacting with the receptor) within the cytokines. This suggests a more dynamic assembly process between leptin and its receptor where the malleability of helix A could affect binding affinity and signaling.
|
Extent |
31 minutes
|
Subject | |
Type | |
File Format |
video/mp4
|
Language |
eng
|
Notes |
Author affiliation: UCSD, CTBP (The Center for Theoretical Biological Physics)
|
Series | |
Date Available |
2014-08-07
|
Provider |
Vancouver : University of British Columbia Library
|
Rights |
Attribution-NonCommercial-NoDerivs 2.5 Canada
|
DOI |
10.14288/1.0043773
|
URI | |
Affiliation | |
Peer Review Status |
Unreviewed
|
Scholarly Level |
Postdoctoral
|
Rights URI | |
Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
Attribution-NonCommercial-NoDerivs 2.5 Canada