Re: What is the function of a protein's prodomain? Why are they called that?

hi Andrei,

The terms that we use to define the various processed states of a protein can certainly be confusing. You have probably seen "pre-" and "pro-", either separately or in combination, in front of "protein", "peptide" or "domain". You may also see "signal" or "leader" in front of "sequence" or "peptide". What does it all mean?

The "pre-" prefix indicates that the N-terminal part of the protein is cleaved when the protein enters a secretory pathway. For a long time, the best-studied secretory process was Sec secretion, used by both eukaryotes and prokaryotes to export proteins out of the cell. The term "signal peptide" or "signal sequence" was used to describe the N-terminal part of the protein that directs this process. Later on, other secretory pathways were discovered (such as those that direct proteins to organelles in eukaryotic cells). Furthermore, there can be N-terminal sequences which are "signals" for non-secretory processes. For a time the term "leader sequence" was popular as a general term for an N-terminal sequence involved with cell trafficking, but this term also refers to the 5'-region of mRNA molecules. So to avoid confusion, "pre-" was adopted as the prefix that means "before N-terminal cleavage during a secretion event". In general, people use "signal peptide" to refer specifically to the Sec pathway.

Further down the research track, it was discovered that many proteins require additional proteolytic processing to become fully functional. This also involves cleavage of a peptide from the N-terminus, but is not part of the secretory process. So the prefix "pro-" was adopted to describe the protein prior to this processing event. This means that you can have a "preprotein" (the N-terminal is cleaved during secretion), a "proprotein" (the N-terminal is cleaved to make the protein active) or a "preproprotein" (the N-terminal is cleaved during secretion, then cleaved again to make the protein active).

Caspase is a good example. It is synthesised as an inactive proprotein. In this case the term "prodomain" is used, because the N-terminal region is folded into a discrete structural unit with a specific function (the definition of a domain). Usually the prodomain mediates interaction with other proteins in a complex. Proteolytic cleavage then removes the prodomain, activates the caspase and triggers a cascade in which caspases activate other caspases, leading eventually to the cleavage of key target proteins (caspase substrates) and cell death. Other proteins besides caspases also contain prodomains that mediate a particular process for the protein.

There is quite a nice summary of caspases (http://en.wikipedia.org/wiki/Caspase) at Wikipedia and a link to more specific caspase information which you may find useful.