Evolution by Protein Domains

1
Evolution by Protein Domains
Lego Ad
Itai Yanai Department of Biology Technion
Israel Institute of Technology
2
How is a novel gene born?

• Domains are the evolutionary units of sequence
  that comprise the gene coding regions.
• Most genes are built from more than one domain.
• Novel genes can be created by recombinations of
  domains into new domain arrangements.

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GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAAC
CCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCAC
AGTTATCCATTTTATGAATGGAGTTheStructureofProteinDomai
nsGATGAAAACCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGAT
ATTAAGACTGAGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTT
GTTCATGAGCACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTG
ACAGAAAAGCCCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTAT
GTATGGAGTTTCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGT
ATCCCATGACTTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGA
CCTTGTCAAATAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAG
ACCCCACAAGTTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATG
ACAATGGCAAGTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCA
ATCGGGGGTTCCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACA
GTTTACGGAACTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAG
GGTCTTATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCA
TTGCAGCCTTGATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCC
TAGTAGCTGAGACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTT
ATTTTTTGTATAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAAT
TCCTGGTCTCAAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATT
ACAGATGTGAGCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCA
TTGTGAAGGATACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTG
GATGCAGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGG
GAGGATCGCTTAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGA
AAACCTGTCTCTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGT
GTTGTGCACCTAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATAC
CTTGAGCTGGGGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGC
CACTGCACTCCAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAG
AAAGATACCCAGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTT
TAGACCCAGCTCCTGCCTCCCAGCCTTCT
4
Myoglobin and Hemaglobin were the first two
protein structures to be solved.
Hemoglobin
Myoglobin
Brenner, S.E. Nature Reviews Genetics. 2001. 2,
801-809
5
Hemoglobin has alpha helices as secondary
structures
hemoglobin
Alpha helix
Protein figures throughout are from
CATH http//www.biochem.ucl.ac.uk/bsm/cath_new/
www.people.virginia.edu/ rjh9u/gif/fig17mod.gif
6
Thrombin has mainly beta sheets as secondary
structures
Thrombin
Beta sheet
www.people.virginia.edu/ rjh9u/gif/fig17mod.gif
7
Proteins were found to have spatially distinct
structural units
TRANSFERASE (METHYLTRANSFERASE) 1adm
8
In 1974, Michael Rossman observes that structural
domains can recur in different structural contexts
1ht0 an alcohol dehydrogenase
1i0z a lactate dehydrogenase
Rossman fold
Rossmann, M.G. et al. (1974). Nature 250, 194199
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Domains can recur in multiple copies in the same
protein
Fibronectin protein1fnf
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Structural definition of domains

• A distinct, compact, and stable protein
  structural unit that folds independently of other
  such units.

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Recurrent domains in diphtheria toxin (1ddt)
The diphtheria toxin is made up of three domains,
each of which is involved in a different stage of
infection (receptor binding, membrane
penetration, and catalysis of ADP-ribosylation of
elongation factor 2). A structural neighbor is
depicted next to each domain of diphtheria toxin
(middle).
Holm and Sander. PROTEINS Structure, Function,
and Genetics 338896 (1998)
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Dominant domain fold types.
Holm and Sander. PROTEINS Structure, Function,
and Genetics 338896 (1998)
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What does fold space look like?

• An All vs. All comparison was done
• A multivariate scaling method to summarize
  relationships
• 5 attractors are detected corresponding to 40 of
  fold space

Holm and Sander. Science (1996) 273 595-
14
SCOP a structural classification of proteins
Domains are clustered into families in which
significant sequence similarity is detected as
well as conservation of biochemical activity.
Updated from Murzin et al. J. Mol. Biol. 247,
536-540.
15
SCOP a structural classification of proteins
Families are in turn grouped into superfamilies
where sequence similarity is still recognizable
and basic biochemical properties are conserved.
Superfamilies and families are monophyletic (deriv
e from a common ancestor)
Updated from Murzin et al. J. Mol. Biol. 247,
536-540.
16
SCOP a structural classification of proteins
A fold is a topology of the folded protein
backbone. Unknown whether superfamilies of the
same fold are monophyletic
Updated from Murzin et al. J. Mol. Biol. 247,
536-540.
17
Distribution of protein folds by the number of
families
There are many folds with 1-3 families, but only
a few folds with numerous families
From Koonin et al. Nature. 420, 218-223
(2002). See also Zhang, C. DeLisi, C. J. Mol.
Biol. 284, 13011305 (1998).
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Estimating the Number of Protein Folds
The total number of folds in globular, water-
soluble proteins is estimated at about 1000. The
sequenced genomes of unicellular organisms encode
from approximately 25, for the minimal genomes
of the Mycoplasmas, to 70-80 for larger genomes,
such as Escherichia coli and yeast, of the total
number of folds. The number of protein families
with significant sequence conservation was
estimated to be between 4000 and 7000, with
structures available for about 20 of these.
Wolf et al. JMB (2000) 299, 897-905
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GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAAC
CCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCAC
AGTTATCCATTTTATGAATGGAGTDomainsfromasequenceaspect
GATGAAAACCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGATAT
TAAGACTGAGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTTGT
TCATGAGCACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTGAC
AGAAAAGCCCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTATGT
ATGGAGTTTCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGTAT
CCCATGACTTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGACC
TTGTCAAATAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAGAC
CCCACAAGTTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATGAC
AATGGCAAGTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCAAT
CGGGGGTTCCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACAGT
TTACGGAACTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAGGG
TCTTATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCATT
GCAGCCTTGATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCCTA
GTAGCTGAGACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTTAT
TTTTTGTATAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAATTC
CTGGTCTCAAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATTAC
AGATGTGAGCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCATT
GTGAAGGATACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTGGA
TGCAGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGGGA
GGATCGCTTAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAAA
ACCTGTCTCTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGTGT
TGTGCACCTAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATACCT
TGAGCTGGGGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGCCA
CTGCACTCCAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAGAA
AGATACCCAGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTTTA
GACCCAGCTCCTGCCTCCCAGCCTTCT
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A domain at the sequence level is defined in
terms of its recurrence across different sequences
21
Sequence biology predominantly proceeds by
decomposing proteins into their domains
Protein sequence families are constructed at the
domain level
Wheelan, S.J. et al. Bioinformatics 16, 613-8
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Detecting domains at the sequence level
From the InterPro database
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Forms of multidomain proteins
colinear
Non-colinear
Most structural domains are colinear within
multidomain proteins
Adams, RM, Das, S and Smith, TF. (1996). Multiple
domain protein diagnostic patterns. Protein
Science 5, 1240-1249.
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The classification of proteins is made difficult
by multidomained proteins
Gene Families The Taxonomy of Protein Paralogs
and Chimeras Steven Henikoff, Elizabeth A.
Greene, Shmuel Pietrokovski, Peer Bork, Teresa K.
Attwood, Leroy Hood Science 1997 October 24 278
609-614.
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Misannotation due to multidomain proteins
Domain of known function
A
Domain of unknown function
B
Annotation
kinase
Multidomain protein C
Kinase-like
Kinase-like
A is similar to C, and C is similar to B, but A
is not similar to B
Smith and Zhang. Nat Biotechnol 1997 151222-3
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Fusion Links
glyQ glyS
E. coli
Fusion link
CT796
C. trachomatis
Glycyl-tRNA synthetase. The fact that glyQ and
glyS interact could have been predicted from the
fusion protein CT796
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Fusion links detect protein-protein interactions
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Correspondence between functional associations
and genes linked by the fusion method
From Glycolysis
M. genitalium PGK
Glycerone-P
M. genitalium TIM
PGK1
M. genitalium GAPDH
Glyceraldehyde-3P
GAPDH
Glycerate-1,3P2
Thermotoga Maritima
PGKTIM
TIM
Glycerate-3P
Phytophthora infestans
TIMGAPDH
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Functional Cascade of Fusion Links
SC putative DHFRs YHR049W, YMR222C and YOR280C
SC DHFR DFR1
SC thymidylate synthetase CDC21
4 yeast proteins

SC hypothetical proteins YKL088W, YKR027C,
YOR054C
The fusions
S. pombe DHFR
Carrot DHFR-thymidylate synthetase
S. pombe thymidylate synthase- like DNA
metabolism protein
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Extracellular matrix proteins are multidomained
A further means of building interaction surfaces
is through the joining of repeated (up to 50)
copies of a small peptide motif, yielding a much
larger structure with multifaceted binding
properties. Pawson Science 2003
Peer Bork, http//www.bork.embl-heidelberg.de/Modu
les/07-matrix.gif
31
Domain accretion
Domain accretion in the evolution of orthologous
sets of eukaryotic genes
C1
Yeasts
C2
Zk
C1
C. elegans
C2
C3
Zk
A. thaliana
C1
C2
C3
Ub
Zk
C1
D. melanogaster
C2
C3
Zk
Koonin et al. Cell. 2000
32
Domain accretion may have been used to in pathway
evolution
Peer Bork, http//www.bork.embl-heidelberg.de/Modu
les/07-matrix.gif
33
Most genes are multidomained
The number of types of domain-types per gene is
exponentially distributed.
Count this gene as having 4 domain-types
Distribution of 8,114 human genes containing
2,347 domain types, according to the Interpro
database.
Inbar Cohen-Gihon, 2004
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Number of domains per gene is power-law
distributed if repeats are included in domain
count.
Count this gene as having 6 domains (including
repeats)
power law f(i) i-k , (k 1-3)

• Power laws describe distributions of a number of
  quantities in biological and other contexts,
  e.g.,the node degrees (number of connections) in
  metabolic and protein interactions networks, the
  Internet and social networks, citations of
  scientific papers, population of cities, personal
  wealth
• Networks described by power laws are known as
  scale-free - they look the same at different
  scales.

Slide by E. Koonin, 2003
35
Domain Architecture Networks A pair of domains
are linked if there is at least one instance of a
protein containing both of the domains.
Apoptosis proteins
The derived domain architecture network
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Domain connection network
1
1
2
2
1
1
6
3
1
5
1
4
3
8
7
2
2
3
4
2
1
2
Frequency distribution of domain-connections
frequency
1 2 3 4 5 6 7 8
degree connectivity
37
Frequency distribution of domain-connections
within a genome follows a power-law distribution
Power-law y x-a (appears linear on a log-log
scale)
Wuchty S. (2001) MBE 18(9) 1694-1702
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The good thing about standards is that there are
so many of them to choose from
Interpro An integrated resource of protein sites
and functional domains
39
Introducing Interpro.
http//www.ebi.ac.uk/interpro/
40
Interpro entry for a zinc finger domain
41
Interpro entry for a zinc finger domain
(continued)
42
Interpro entry for a zinc finger domain
(continued)
43
Super-families of domains in Interpro (analogous
to superfamilies in SCOP)
44
Some domains actually contain other domains!
45
Supra-domains Evolutionary units larger than
single domains
N-terminal end
C-terminal end
Each represents a different domain architecture
Supra-domain of size 2 and 3
A supra-domain is defined as a domain combination
in a particular N-to-C-terminal orientation that
occurs in at least two different domain
architectures in different proteins with (i)
different types of domains at the N and
C-terminal end of the combination or (ii)
different types of domains at one end and no
domain at the other.
Vogel C. J Mol Biol. 2004 336 (3) 809-23
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Supra-domains Evolutionary units larger than
single domains
The P-loop containing nucleotide triphosphate
(NTP) hydrolase domain and the translation
protein domain occur as one combination in
several different translation factors. This
supra-domain occurs in 35 different domain
architectures, and five of these are given here.
Chothia C. Science 2003 300 1701-1703 Vogel C. J
Mol Biol. 2004 336 (3) 809-23
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Supra-domains in Src and Abl
The Order of Domains in the Polypeptide Chains of
Src and Abl, and Diagrams of Their Assembled,
Autoinhibited StatesIn both cases, the SH3-SH2
clamp fixes the bilobed kinase domain in an
inactive conformation. The domain color codes are
SH3, yellow SH2, green kinase small lobe, dark
blue kinase large lobe, light blue. The
activation loop in the large lobe is red.
Connector, linker, and N- and C-terminal
extensions are black. In Bcr/Abl, gene fusion has
replaced the Abl cap by a long segment of Bcr.
Harrison, S. C. (2003). Cell, 112, 737740.
48
GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGATGGCATATTTTGTTCAGGGAATGGTGAATTAAGTGT
GGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAGTCAAATAG
TTTGGAACAGGTATAATGATCACAATAACCCCAAGCATAATATTTCGTTA
ATTCTCACAGAATCACATATAGGTGCCACAGTTATGGAGTSignalinga
ndMulticellularityAAACCTTAGGAATAATGAATGATTTGCGCAGG
CTCACCTGGATATTAAGACTGAGTCAAATGTTGGGTCTGGTCTGACTTTA
ATGTTTGCTTTGTTCATGAGCACCACATATTGCCTCTCCTATGCAGTTAA
GCAGGTAGGTGACAGAAAAGCCCATGTTTGTCTCTACTCACACACTTCCG
ACTGAATGTATGTATGGAGTTTCTACACCAGATTCTTCAGTGCTCTGGAT
ATTAACTGGGTATCCCATGACTTTATTCTGACACTACCTGGACCTTGTCA
AATAGTTTGGACCTTGTCAAATAGTTTGGAGTCCTTGTCAAATAGTTTGG
GGTTAGCACAGACCCCACAAGTTAGGGGCTCAGTCCCACGAGGCCATCCT
CACTTCAGATGACAATGGCAAGTCCTAAGTTGTCACCATACTTTTGACCA
ACCTGTTACCAATCGGGGGTTCCCGTAACTGTCTTCTTGGGTTTAATAAT
TTGCTAGAACAGTTTACGGAACTCAGAAAAACAGTTTATTTTCTTTTTTT
CTGAGAGAGAGGGTCTTATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCA
GTCATAGCTCATTGCAGCCTTGATTGTCTGGGTTCCAGTGGTTCTCCCAC
CTCAGCCTCCCTAGTAGCTGAGACTACATGCCTGCACCACCACATCTGGC
TAGTTTCTTTTATTTTTTGTATAGATGGGGTCTTGTTGTGTTGGCCAGGC
TGGCCACAAATTCCTGGTCTCAAGTGATCCTCCCACCTCAGCCTCTGAAA
GTGCTGGGATTACAGATGTGAGCCACCACATCTGGCCAGTTCATTTCCTA
TTACTGGTTCATTGTGAAGGATACATCTCAGAAACAGTCAATGAAAGAGA
CGTGCATGCTGGATGCAGTGGCTCATGCCTGTAATCTCAGCACTTTGGGA
GGCCAAGGTGGGAGGATCGCTTAAACTCAGGAGTTTGAGACCAGCCTGGG
CAACATGGTGAAAACCTGTCTCTATAAAAAATTAAAAAATAATAATAATA
ACTGGTGTGGTGTTGTGCACCTAGAGTTCCAACTACTAGGGAAGCTGAGA
TGAGAGGATACCTTGAGCTGGGGACTGGGGAGGCTTAGGTTACAGTAAGC
TGAGATTGTGCCACTGCACTCCAGCTTGGACAAAAGAGCCTGATCCTGTC
TCAAAAAAAAGAAAGATACCCAGGGTCCACAGGCACAGCTCCATCGTTAC
AATGGCCTCTTTAGACCCAGCTCCTGCCTCCCAGCCTTCT
One of the key problems of becoming a
multicellular organism is solving the problem of
cell signaling.
49
The Monosiga brevicollis genome
M. brevicollis is a choanoflagellate which are
the closest known relatives of metazoans. They
are free-living unicellular and
colonial flagellate eukaryotes
from Wikipedia
The M. brevicollis genome is 42Mb containing
9,200 genes.
flagellum
collar of actin-filled microvilli
King et al. Nature 2008 451 783
50
The genome encodes cell adhesion and signalling
protein domains formerly thought to be restricted
to metazoans.
Phylogenetic distribution of metazoan-type cell
adhesion domains and sequence-specific
transcription factor families. M. brevicollis
possesses diverse adhesion and ECM domains
previously thought to be unique to metazoans
(magenta). In contrast, many metazoan sequence
specific transcription factors are absent from
the M. brevicollis gene catalogue.
King et al. Nature 2008 451 783
51
Domain shuffling and the evolution of Notch
signaling
Cassettes of protein domains found in metazoan
Notch receptors (EGF, NL and ANK (ankyrin
repeats)) are encoded on separate M. brevicollis
genes in arrangements that differ from metazoan
Notch proteins, and definitive domains, such as
the NOD domain are absent.
King et al. Nature 2008 451 783
52
Phosphorylation can reversibly alter the activity
of an enzyme through the combined action of a
protein kinase and a protein phosphatase.
p
kinase
phosphotase
inactive
active
inactive
53
Tyrosine phosphorylation is a major mechanism of
transmembrane signaling.
Protein tyrosine kinases (PTKs) add phosphate to
tyrosines
Pawson and Scott. Scientific American (2000)
54
SH2 domains (Src-homlogy 2)
SH2 domains are modules of 100 amino acids that
bind to specific phospho (pY)-containing peptide
motifs
The Pawson Lab http//www.mshri.on.ca/pawson/domai
ns.html
55
Protein phosphorylation regulates proteinprotein
association
SH2 domains bind to the phosphorylated tyrosines
Pawson and Scott. Scientific American (2000)
56
The SH2 domain is found embedded in a wide
variety of metazoan proteins that regulate
functionally diverse processes.
Pawson, T. et al., Trends in Cell Biology Vol.11
No.12 December 2001
57
Protein modules for the assembly of signaling
complexes
Several modular domains have been identified that
recognize specific sequences on their target
acceptor proteins.
Pawson Scott. Science (1997) 278 2075-2080
58
The building blocks modular interaction domains
in signal transduction
Pawson Nash. Science (2003) 300 445-452
59
The physical linkages among protein domains
differ significantly between M. brevicollis and
metazoans
A metric for functional usage of a domain within
a genome is the number of other domains with
which it co-occurs in a single protein. Numbers
of pairwise domain combinations are indicated for
classes of signalling domains. All combinations
observed in M. brevicollis are indicated either
as those that are only observed in the M.
brevicollis genome (magenta) or as those that are
observed both in M.brevicollis and metazoan
genomes (grey).
Abundant domain shuffling followed the separation
of the choanoflagellate and metazoan lineages.
King et al. Nature 2008 451 783
60
Evolution by Protein Domains
At the structural level, a domain is a distinct,
compact, and stable protein structural unit that
folds independently of other such units. A study
of the protein universe reveals a limited set of
recurring domains. Most genes have multiple
domains occur in many contexts. M. brevicollis,
a choanoflagellate, encodes cell adhesion and
signalling protein domains formerly thought to be
restricted to metazoans, however the domain
combinations differ significantly between M.
brevicollis and metazoans. Signalling protein
domains are important for multicellularity.