Adapter Domains

Question 1

Examples of functions of interaction domains:

Answer 1

1. Determine subcellular localization and trafficking of proteins
2. Mediate docking onto specific sites of post-translational modification
3. Adapters that link distinct proteins into a common pathway
4. Orderly assembly and disassembly of multi-protein complexes
5. Directing the substrate specificity of enzymatic domains

Question 2

Therapeutic possibilities for protein-protein interactions:

Answer 2

1. Stabilise
2. Induce (Re-wire)
3. Block

Question 3

General properties of interaction domains:

Answer 3

Typically, interaction domains are independently-folding modules of 35-150 amino acids
- Interaction domains lack intrinsic enzyme activity (though other domains in the same proteins may be enzymatic)
- Serve as linkers between signalling components
Retain their binding properties when expressed independently
- Have juxtaposed N- and C-termini that allows their easy insertion (in evolution) into a loop on a pre-existing protein
- SH2, PDZ, PTB domains have structurally similar 3-D folds with anti-parallel beta sheets flanked by one or two alpha-helices, but different binding specificities.i.e., this overall structure is adaptable in evolution in terms of being able to incorporate binding pockets that dock onto different types of binding motif.

Question 4

SH2 Domain

Answer 4

“The prototypical phospho-recognition module”
- Binding site lies across the sheet structure flanked by the two helices
- Conventional SH2 domains have a conserved deep pocket (with Arg) that recognizes pY, and a more variable specificity pocket that binds 3-6 residues C-terminal to the pY. (Acts like a plug socket)
- SH2 proteins localize to tyrosine-phosphorylated sites
(requires tyrosine kinase receptor activation)
- Certain SH2-containing intracellular signaling proteins can bind to activated PDGF receptors

Question 5

v-Src, C-Src

Answer 5

v-Src = Viral (from "Rous sarcoma virus")
c-Src = Cellular 

C-Src has two modes of intrinsic inhibition by interactions between:

1. SH2 domain and phosphorylated Y527
2. SH3 domain and polyproline region

v-Src lacks the C-terminal tail containing the inhibitory phosphoY527:

• Kinase is active as a tyrosine kinase (SH1)
• SH2 interacts with pY on targets
• SH3 interacts with polyproline on targets

Question 6

Examples of modular interaction domains in cellular regulation:

Answer 6

Domain-Peptide Motif:

• PTB Domains
• Bromodomains

Domain-Phospholipid:

• FYVE
• PH

Domain-Domain: (recognise domains of the same time i.e. PDZ domains binds to PDZ domain)

• PDZ domains
• Death domains