sequence's ends -- crucial to protein folding too?

Frank Küster geb. Fürst ffrank at
Fri Sep 20 04:03:57 EST 2002

"Artem Evdokimov" <AEVDOKIMOZ at> schrieb:

> > > Cutting/adding/mutating residues at the termini is VERY OFTEN bad for
> the
> > > folding. Keep in mind that oftentimes having extra residues is bad
> > > too.
> >
> > I would have argued that this is rather a question of solubility,
> > i.e. "sticky ends" of a protein aggregate? Can you give some examples?
> Sorry, but no :) These proteins are related to my current proprietary work
> and I can't disclose them without risking to be fired. 

I understand. One time they'll be in pdb, I hope.

> I would agree that in
> many cases the problem lies in the solubility, but not always. Specifically,
> when you're truncating a transmembrane domain from a cytosolic catalytic
> domain, there is a significant risk of misfolding if the cut is not
> accurate. 

I see. In this case, it seems the interaction between the domains or the
cytosolic domain and the membrane are crucial for folding, or at least
for stability. It's not so easy with domain proteins, anyway. Sometimes
the domains act just like independent entities (or even exist as such?
I'm sure there must be examples), sometimes the stabilization comes
mainly from interdomain-interactions. 
> > Hm. If you don't cut enough, you get loose termini, which don't
> > interfere with folding (because this is the near-native sequence), but
> > inhibit crystallization. If you cut too much, you get a problem because
> > you cut beyond the "terminus" and deleted a residue that is in the bulk
> > of the structure. That's how I see it..
> This makes sense, however let's not forget other likely (parallel)
> scenarios: imagine that you have left a few extra hydrophobic (or
> mixed-type) residues at the N-terminus - chances are that they will tend to
> aggregate and assume non-native conformations shortly after their emergence
> from the ribosome. This can create a 'nucleus of misfolding' if you wish,
> which will drag the rest of the sequence into a free energy hole from which
> it may never climb out. With the C-terminal residues, the situation is not
> as severe but there are still possible problems with sequences that do not
> fold spontaneously and require chaperonins and related molecules.

You're right. Things are always more complicated if you look closer. One
other example, kind of extreme, comes to my mind: Pro-domain assisted
folding, e.g. in alpha-lytic protease, which is less stable than the
unfolded form after the pro-domain has been cleaved.

Bye, Frank
sigmentation fault

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