Very ‘sticky’ proteins – not too sticky after all?

Most protein biochemists and cell biologists know sticky proteins just too well. They are a pain to work with. They hang on to chromatography and antibody capture resins. When expressed in recombinant form, they form monstrously sized aggregates and bind to a plethora of irrelevant proteins from E. coli or other host cells. It seems a fair guess that thousands of scientific papers are fatally flawed by reporting supposedly specific but in reality entirely nonspecific interactions of VSPs.In some cases, the stickiness is artificially inflicted by intentional protein modification, for example by the addition of a tag onto the protein in a bad spot, or by expressing inappropriate fragments that expose hydrophobic core regions. But even when great care is taken to avoid this, it appears that many proteins live their lives as molecular ‘glue balls’. How can they function in cells without disturbing the system? How can they not get permanently stuck when intracellular protein concentrations are often in excess of 200？mg/ml (a property that leads to an ‘extreme cuddling’ phenomenon known as macromolecular crowding)? How can they seemingly retain their stickiness for, in some cases, hundreds of million years of evolution?The simple answer could be: many of them may not be so sticky after all when observed in their undisturbed natural habitat. We need to appreciate much more how different most experimental conditions that we routinely use are compared to the normal environment of proteins. In addition to a frequent lack of appropriate protein modifications on recombinant proteins, which, if present, could make proteins less sticky in vivo, possibly the greatest determinant in cells that prevents nonspecific stickiness is the intracellular compartmentalization of naturally occurring proteins in space and time.We propose that we must forever say ‘Goodbye’ to the belief that most intracellular proteins float about their business like dumplings in a soup. This notion has been ch