Back to "Biological Language Modeling Seminar Topics"
Reference: www.mshri.on.ca/pawson/research1.html
Back to "Protein protein interactions"
Protein protein interaction domains in signal transduction
Larger databases that contain this topic as a subset:
see links
Pattern and Profile Searches, e.g. PROSITE profiles http://us.expasy.org/cgi-bin/prosite-list.pl#domains
Posttranslational Modifications
Function of Interaction domains:
- to form specific multi-protein complexes that couple cell surface receptors to intracellular biochemical pathways that control cellular responses to external signals.
How?
- signal transduction pathways usually involve a series of protein-protein interactions,
- recruit and confine signaling proteins to an appropriate subcellular location,
- determine the specificity with which enzymes interact with their targets, e.g. association of protein kinases and their substrates.
Modular character of protein protein interaction domains in signal transduction
- typically, protein-protein interaction domains are independently folding modules of 35-150 amino acids, therefore structure of many of them are available
- their N- and C-termini are usually close together in space, while their ligand-binding surface lies on the opposite face of the domain. This arrangement allows the domain to be inserted into a host protein while projecting its ligand-binding site to engage another polypeptide.
- multiple domains can be assembled in a single protein
Families of protein-protein interaction domains
- based on sequence similarity
- based on ligand-binding properties
computational estimate:
- at least 1394 distinct interacting domains in the DIP (see Figure 1 in Bock and Gough (2001))
- average 481 + 386 domain length (as predicted by Pfam) (see Figure 1 in Bock and Gough (2001))
- Most frequent protein domains in the interaction dataset, as predicted by the Protein Families Database (Pfam) (see Table2 in Bock and Gough (2001))
?? This will also include non-protein protein interaction domains, doesn't it??? For example a kinase interacting with a receptor will show the kinase domain by this approach, which is NOT the domain of interaction.
Motifs that are recognized by protein protein interaction domains:
A. Short peptides
B. Extensive protein-protein interaction domain interfaces (homo- or heteromultimers)
Examples for short peptide motifs:
- with secondary modification
1. phosphotyrosine-containing motifs,
- Examples for protein who carry this motif: activated receptors for growth factors, cytokines and antigens.
- Recognizing protein protein interaction domain:
a. SH2 domains
b. PTB domains, also binds unphosphorylated peptides
2. phosphoserine/threonine motifs,
- Recognizing protein protein interaction domain:
b. FHA domains
c. WW domains, also binds unphosphorylated peptides, see below Proline-rich
d. WD40-repeat domains
3. acetylation of lysine residues
- Proteins who carry the motif: histones
- Recognizing proteins: creates binding sites for the Bromo domain
4. methylation of lysine residues
- Proteins who carry the motif: histones
- Recognizing proteins: creates binding sites for the Chromo domains,
- without requirement for secondary modification
1. Proline-rich
- Recognizing protein domains:
a. SH3
b. WW
c. EVH1
2. PDZ domain motifs
- PDZ domains bind the extreme C-termini of other polypeptides, such as ion channels and receptors, in a fashion that appears important for the localization of their targets to particular subcellular sites, as well as for downstream signaling.
Example: G protein coupled receptors
Other protein-protein interaction domains:
Apoptosis
Chromatin
Proteolysis
Dimerization
Vessicle Traffic
Undefined
Miscellaneous
Examples for extensive protein-protein interaction domains:
Protein-lipid interactions:
In addition to interaction domains that engage specific peptide motifs, a
growing number of modules have been identified that recognize selected
phospholipids, notably phosphoinositides (PI). Strikingly, PH domains can bind
either PI-4,5-P2 or PI-3,4,5-P3, and thereby mediate the effects of lipid
kinases and phosphatases on cellular function. Such phospholipid-binding domains
serve both to concentrate signaling proteins at specific subregions of the
plasma membrane, and to regulate the enzymatic activities of their host
proteins, either directly or by co-recruitment of another regulatory protein.
Modules such as FYVE domains can recognize PI-3-P, and may play an important
role in the trafficking of proteins within the cell.
Phospholipid
Structural relation between protein protein interaction domains:
Although PTB domains primarily bind peptide motifs and PH domains recognize phosphoinositdes, they have a very similar structural fold, which is shared by other interaction domains, including EVH1 domains which bind specific proline-rich sequences. It seems that the PH/PTB/EVH1 domain fold provides a framework that can be used for multiple distinct types of intermolecular interactions.