on the evolution of membrane proteins
DESCRIPTION
On the evolution of membrane proteins. Homology detection Blast, PSIBLAST are they good ? SHRIMP (Bernsel, submitted) Evolution of TM-helices Internal duplications >50% of +6TM proteins. Problems with homology detection of TM proteins. Methods optimized on globular proteins - PowerPoint PPT PresentationTRANSCRIPT
Arne Elofsson ([email protected])
On the evolution of membrane proteins
Homology detection Blast, PSIBLAST are they good ? SHRIMP (Bernsel, submitted)
Evolution of TM-helices Internal duplications
>50% of +6TM proteins
Arne Elofsson ([email protected])
Problems with homology detection of TM proteins
Methods optimized on globular proteins High scoring false positives due to
similarity between unrelated TM regions Hedman et al, 1998 (Pmembr):
Fold recognition methods improve this fact Globular detections improved by profile-
profile (HMM-HMM) comparisons
Arne Elofsson ([email protected])
How does TM proteins evolve
Mutation rates any differences in respect to the different compartments.
Few “multi-domain” membrane proteins
Many complexes
Internal symmetry
Arne Elofsson ([email protected])
Internal duplications on sequence level
Searched for internal duplication events in 87 prokaryotic genomes
Out of 38,124 membrane proteins, 377 duplication events could be detected (~1%)
Internal duplications has been hard to detect on sequence level
α α α α α α
X A B C
J. Mol. Biol. 2004, 339:1-15
Arne Elofsson ([email protected])
Internal symmetry in α-helical inner membrane proteins
2-fold symmetry axis Parallel to membrane
Odd number of TMH Domains anti-parallel to
each other
In plane with membrane Even number of TMH Domains parallel to each
other
N
middle
C
C N
Parallel:LacYGlpTSav1866 ABC transporterAcrBEmrDADP/ATP carrier
Antiparallel:LeuTSecYBtuCDAQP1GlpFAmtBClC H+/Cl- exchange transporterNhaA
Arne Elofsson ([email protected])
Many (most) proteins have internal duplications
6 8 10 12
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Fraction of chains with internal duplications
Number of transmembrane helices (minimum)
Fra
ction c
onta
inin
g a
duplic
ation
Arne Elofsson ([email protected])
Duplications in TM proteins
Distribution of duplication size
0,00%10,00%20,00%30,00%40,00%50,00%60,00%70,00%80,00%90,00%
100,00%
6 7 8 9 10 11 ≥12
Number of transmembrane helices in chain
No duplication
6 TMH
5 TMH
4 TMH
3 TMH
Arne Elofsson ([email protected])
Both parallel and antiparallel duplications exist
Parallel / Antiparallel duplications
0
1
2
3
4
5
6
3 4 5 6
Number of duplicated helices
Antiparallel
Parallel
Arne Elofsson ([email protected])
But in order to have antiparallel domains, they must be inserted with opposing topology!
• In order for an antiparallel symmetry to be explained by a duplication event, each subunit of the homodimer must be inserted with opposite topology
• That implies that a sequence can have dual topology, be inserted either way in the membrane
• Have been constructed in labs (Cell 62, 1135-1141 & Cell 77, 401-412)
inside
outside
membrane
N
C N
C
Arne Elofsson ([email protected])
Hypothesis for antiparallel internal symmetry
Nat. Struct. Mol. Biol. 2006, 13: 94-96
Arne Elofsson ([email protected])
Detection of internal duplications
Structural alignments Finds most of the manually detected
examples. Sequence alignments
Sequence alignments do not find most. Using SHRIMP about 80% can be found Also finds a few extra. Some problems defining exact duplication
unit Genome scanning
Ongoing.
Arne Elofsson ([email protected])
Acknowledgements
Erik Granseth Anni Kauko Jenny Falk Andreas Bernsel Kristoffer Illergård
Arne Elofsson ([email protected])
Final comments
Thanks to EMBRACE Please fill out the questionaire..