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Modular proteins I. Level 3 Molecular Evolution and Bioinformatics Jim Provan. Patthy Sections 8.1.1 – 8.1.3. Protein domains. Folded structures of proteins that are larger than 200-300 residues generally consist of multiple structural domains :

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modular proteins i

Modular proteins I

Level 3 Molecular Evolution and Bioinformatics

Jim Provan

Patthy Sections 8.1.1 – 8.1.3

protein domains
Protein domains
  • Folded structures of proteins that are larger than 200-300 residues generally consist of multiple structural domains:
    • Compact, stable units with a unique three-dimensional structure
    • Interactions within a domain are more significant than those between domains
    • Fold independently i.e. structural domains are also folding domains
    • If domain performs distinct function which remains intact in the isolated domain, then it is also a functional domain
  • Many multidomain proteins are homomultimeric i.e. contain multiple copies of a single type of structural domain:
    • Arisen through internal duplication of complete domains
    • Fate of domains determined by similar rules to paralogous genes
protein domains3
Protein domains
  • Many multidomain proteins are heteromeric:
    • Example is plasminogen activator where a trypsin-like serine protease is joined to kringle, finger and EGF domains
    • May occur by fusion of two or more genes (chimeric proteins)
    • Also known as modular proteins, with domains known as modules
  • Certain modules occur in a wide variety of hetero- and homomultimeric proteins:
    • Suggests mechanisms to facilitate duplication and dispersal
    • “Building blocks” of different types of multidomain proteins are known as mobile protein modules
    • Frequency of transfer and incorporation into new protein reflects fixation probability
modular assembly by intronic recombination
Modular assembly by intronic recombination
  • Discovery of introns provided potential new mechanisms for protein evolution:
    • Gilbert suggested that recombination within introns could assort exons independently
    • Idea of rapid construction of novel genes from parts of old ones led to the formulation of the exon-shuffling hypothesis
  • According to “introns early” theories, all extant genes were constructed from a limited number of exon types
  • Under the “introns late” theory, intronic recombination and exon shuffling could not have played a major role in the assembly of the earliest genes
  • Original theory was that exons corresponded directly to modules and/or structural motifs
problems with the introns early hypothesis
Problems with the “introns early” hypothesis
  • In the case of many genes, no obvious correspondence was observed between protein structure and intron location
  • It is now known that introns can also be inserted into genes i.e. structure of a gene may not be its original structure
  • Introns suitable for exon shuffling did not originate until a relatively late stage of eukaryotic evolution
  • Exon shuffling has only been conclusively demonstrated in “young” proteins unique to higher eukaryotes
  • Only a special group of exons, the “symmetrical” modules, are really valuable for exon shuffling. Intron phase distribution is also a crucial factor.
self splicing introns
Self-splicing introns
  • Group I introns:
    • Reaction requires only a guanine nucleotide cofactor:
      • Provides a free 3’-OH group that attacks the 5’ splice site
      • 3’-OH generated at the end of the upstream exon
      • Second transesterification joins the two exons
    • Crucially depends on folded structure of the intron itself
  • Group II introns:
    • Does not require an external cofactor: 2’-OH of an adenine within the intron cuts the 5’ splice site
    • 2’5’ phosphodiester bond (branch site) forms the lariat structure
    • Although folding is still crucial, chemistry, sequence of events and lariat formation are similar to nuclear spliceosomal introns
spliceosomal introns
Spliceosomal introns
  • Spliceosomal introns are only spliced in the presence of a complex of specific proteins and RNA known as a spliceosome
  • Majority of intron is unimportant: as long as the 5’ and 3’ splice sites and the branch site are conserved, splicing can take place:
    • Large insertions into spliceosomal introns, or deletions do not affect splicing efficiency
    • Chimeric introns, containing the 5’ end of one intron and the 3’ end of another, are also properly spliced
    • Mutations (directed or otherwise) in these regions lead to aberrant splicing
  • Spliceosomal intron plays a minor role in its own splicing: the actual spliceosome complex is more important
evolution of spliceosomal introns
Evolution of spliceosomal introns
  • Both group I and group II self-splicing mechanisms resemble spliceosome catalysed splicing:
    • Initial step is attack by ribose hydroxyl group on 5’ splice site
    • In each case, reactions are transesterifications where phosphate moieties are retained in products
    • In group II and spliceosomal introns, intron is released as a lariat
  • Accepted that spliceosomal-catalysed splicing evolved from group II self-splicing introns :
    • Key step was transfer of catalytic role from intron to other molecules
    • Formation of spliceosome gave spleceosomal introns structural freedom as they no longer had to fulfil the catalytic function
  • Generally found only in nuclear genomes of higher eukaryotes (plants, animals and fungi)
intron loss
Intron loss
  • Plays a significant role in changing exon-intron structure of genes
  • Introns may be eliminated through mechanism that gives rise to processed genes (retroposition)
  • Reverse transcription can also lead to loss of only some introns:
    • Reverse transcription of perfectly spliced mRNA and recombination with the functional gene: mutates original gene
    • Partially processed pre-mRNA could give rise to a semi-processed gene: generates a new paralogue
exon shuffling via recombination in introns
Exon shuffling via recombination in introns
  • Believed that insertion of exons may occur by the same mechanism as insertion of introns:
    • Exon shuffling may be a consequence of the occasional inclusion of exon sequences in the insertion cycle of introns
    • Alternative splicing (exon skipping during splicing) may yield exons with flanking introns
    • If such a composite is inserted into the genome by the same mechanism that inserts single introns (reverse splicing) we have exon shuffling
  • Key difference between intronic recombination model and retrotransposition model:
    • In first case, insertion occurs into a pre-existing intron of same phase as introns flanking exon
    • Retrotransposition model does not have this requirement
evolution of tissue plasminogen activator

S

G

K

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F

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K module duplication

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F

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K

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Evolution of tissue plasminogen activator
evolution of factor xii

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G

K

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Duplication of G module

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G

G

K

P

F

S

G

F

G

K

P

FN2

S

FN2

G

F

G

K

P

Evolution of Factor XII