n-glycosylation: one pathway, two selective constraints
Post on 01-Dec-2014
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Distribution of events of positive selection and population differentiation in a metabolic pathway: the
case of asparagine N-glycosylation
Our hypothesis
Selective constraints are not uniform among positions of a pathway
Genes in upstream positions, or with an higher number of interactions, should be more selectively constrained than others
Pathway-level analysis
Pathway databases are not yet ready for large scale analysis
Too many false positives in the annotations The same annotation can have multiple
interpretations
So, the best approach is to focus on single pathways, one at a time
The pathway of NGlycosylation is a good start for studying how selective constraints are related to pathway position and degree
What is Glycosylation?
Glycosylation is a common form of posttranslational protein modification
Almost 50% of the proteins in SwissProt are glycosylated
(mostly membrane, secreted, signal proteins)
Glycosylation increases the protein's stability and is frequently used as a signal
N-glycosylation(upstream part)
Linear pathway Produces a single sugar
called “NGlycan precursor”
This sugar is required for the proper folding of most membrane proteins
Adapted from Stanley, P., Schachter, H., & Taniguchi, N. (2009). N-Glycans. Essentials of Glycobiology.
N-Glycosylation(upstream part)
The product of the upstream part of the NGlycosylation pathway is used as a “label” for the folding status of proteins.
Folded proteins are marked with
Unfolded proteins are marked with or
N-Glycosylation(downstream part)
Complex pathway composed by thousands of reactions
Produces multiple sugars, important for celltocell interactions
Hossler, P., Mulukutla, B. C., & Hu, W.-S. (2007). Systems analysis of N-glycan processing in mammalian cells. PloS one, 2(1), e713. doi:10.1371/journal.pone.0000713
N-Glycosylation(downstream part)
Protein A
Surface of linfocite
Protein A
Surface of erithrocite
The products of the downstream part of the NGlycosylation pathway are used to “decorate” proteins on the membrane
Downstream part of Glycosylation is involved in
immunity
Protein A
Surface of host's cell
Protein A
Surface of pathogen
Resume: structure of N-glycosylation pathway
Upstream: linear and conserved among species Downstream: complex and related to immunity Hypothesis: genetic diversity should be higher in
the downstream part.
Results
Signatures of high F
ST are more
frequent in the downstream part of the pathway
iHS signals are more or less equally distributed
My group!
● Jaume Bertranpetit (PI)● Hafid Laayouni (my
supervisor)● Ludovica Montanucci● Pierre Luisi● Brandon Invergo● Marc Pybus● Ferran Casals● Martino Colombo
Protein A
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