Someone asked me a question about protein charge and I ended up stumbling upon a couple of really interesting (and open-access) papers about the pI’s of human proteins… And proteins from other organisms. Basically, where a protein is located in a cell, and what the protein hangs out with, impacts what charge the protein would ideally have. And this is reflected in the pI values of the proteins. The pI is that pH at which a protein is neutral overall. When you go to a pH higher than the pI (more basic/alkaline conditions), the protein is net-negative. And if you go to a pH lower than the pI (more acidic conditions), the protein is net-positive. Because the pH differs in different compartments (e.g. lysosomes are acidic, nuclei are more neutral), the pIs of proteins in those compartments are different. Proteins don’t “want” to be totally neutral because then they’re typically unsoluble and clump up. But they also don’t “want” to be “too charged” because then they’ll either be attracting or repelling all sorts of stuff. So proteins often have pI’s around the pH of their environment. And since that environment differs from protein to protein, so do their pIs. Proteins in lysosomes, for example, tend to be more acidic (have low pIs) and those in nuclei tend to be more basic (have higher pIs). Also, proteins in negatively-charged membranes tend to be more basic (so they’re more +-charged normally and therefore can hang with those negatively-charged phospholipid heads) and those that hang out with DNA or RNA tend to be more basic too (so they can hang with the negatively-charged nucleic acid backbone).

note: Hope I got everything correct – this is at least my understanding and interpretation of things. One correction – apparently the nucleus is pretty neutral, not basic, but the proteins in it are – thanks to all that negatively-charged DNA it needs to hang out with. Sorry for any confusion!

Here are links to those papers: 

Kurotani, A., Tokmakov, A.A., Sato, KI. et al. Localization-specific distributions of protein pI in human proteome are governed by local pH and membrane charge. BMC Mol and Cell Biol 20, 36 (2019). 

Lukasz Pawel Kozlowski, Proteome-pI 2.0: proteome isoelectric point database update, Nucleic Acids Research, Volume 50, Issue D1, 7 January 2022, Pages D1535–D1540,

And here’s the proteome-pI database to explore: 

Here’s more about isoelectric points:  &  

Here’s more about native & blue-native PAGE: see ; YouTube: 

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