Protein Structure and Function Lecture 4 Notes: Protein-Protein Interactions Protein-Protein Interactions - The central dogma of molecular biology is the flow of information from DNA to RNA to proteins. This process involves many proteins. - Protein-protein interactions (PPI) are defined as a specific physical contact with molecular docking between proteins that occur in a cell or living organism in vivo. This is not a functional contact (e.g. ribosomal proteins and the newly synthesised protein). - The interaction interface is intentional (not accidental, i.e. the result of specific biomolecular events/forces). The interaction interface is also non-generic; it has evolved for a specific purpose distinct from totally generic functions (e.g. protein synthesis, folding, degradation), not generic contact (e.g. with ribosomes, chaperones, proteases, etc.). There exist stable and transient PPIs. - Protein-protein interactions in protein processing is involved with: (a) Cleavage (b) Modifications (PTM) (c) Folding (d) Targeting/trafficking (e) Degradation - There are a huge variety of protein functions, many of which depend on PPI or are conveyed through PPI or protein networks (many are huge). A protein interactome is a complete set of P-P interactions in a particular cell. - Diseases are often caused by or involve changes in PPI (e.g. protein aggregation in protein misfolding diseases) - Understanding of the protein interactions and networks provides deeper insights into the molecular machinery underlying complex phenotypes, into protein function, into functional and metabolic pathways. - Some protein assemblies are stable macromolecular protein complexes such as all multi- subunit proteins (e.g. glutamate receptors, voltage dependent Kv, ATPase) which do not normally dissociate (quaternary structure). - Other protein assemblies are only built to carry out transient (temporary) actions and can form/breakdown transiently (e.g. binding of transcription factors). - During transcription, there is a multi-subunit general transcription apparatus consisting of: (a) RNA polymerase II core complex (consists of a few proteins, slides along the DNA and synthesises RNA) (b) General transcription factors (e.g. TFIID, identify which genes will be transcribed) (c) Multi-subunit co-factors (d) Chromatin modifying complexes - These complexes temporarily assemble/disassemble in response to stimuli as part of the transcription process. - Another example of protein-protein interactions is the process of protein transport through the ER membrane, signalled by the signal recognition particle (SRP, transient PPI). Peptides synthesised at the ribosome may have signal peptides which is recognised by SRPs, a complex of six proteins and one RNA molecule. This particle interacts with the signal peptide
if it emerges from the ribosome and will guide the ribosome and newly synthesised protein to the SRP receptor (docking is mediated by the RNA). The SRP receptor is a transmembrane receptor present in the ER membrane which consists of an alpha and beta protein (i.e. heterodimer, example of stable PPI). The signal peptide is threaded through the opening channel of the SRP receptor, bringing the polypeptide along, and is then cleaved (catalysed by signal peptidase). - SRP54 is a hydrophobic, alpha-helical protein responsible for the recognition (and binding) of the signal peptide within the SRP protein complex. This