Because they partition efficiently into
membranes while having a molecular shape
different from that of lipids, detergents stress
the membrane/water interface, which they
tend to bend. Ultimately, if the detergent is
“strong” enough, the planar structure becomes
energetically unfavorable, holes form, and
membrane constituents become dispersed into
mixed micelles comprising detergent, lipids,
and MPs. For a detergent to be solubilizing,
the membrane has to break up before micelles
of pure detergent appear in the solution. If
such is not the case, membranes into which
some detergent has partitioned will coexist
with micelles. This happens with some “weak”
detergents and with non-detergent surfactants.
For detergents to efficiently resolve a
membrane into its constituents, protein/
detergent and lipid/detergent interactions
have to overcome the protein/protein, protein/
lipid, and lipid/lipid interactions that keep
the membrane together. Detergents used to
solubilize biological membranes are, therefore,
out of necessity dissociating.
It has long been observed that, once exposed
to detergents, most MPs rapidly lose their functionality
(for two examples among hundreds
of studies, see, e.g., References 6 and 7). Why
this is so is seldom studied in detail, is probably
variable from one protein to the next, and is
not the object of a consensus among membrane
biochemists (for reviews, see, e.g., References
8–11). An extensive discussion of this matter
is beyond the scope of the present review, and
I present only my own views about it. Much
of the data that my coworkers and I have
collected in the course of more than 30 years
of work with half-a-dozen MPs suggests that
a major contribution to the destabilization of
MPs by detergents is the dissociating properties
of the latter, i.e., their ability to disrupt
protein/protein and protein/lipid interactions,
a property that is the very reason why they
are used in the first place. Protein/protein and
protein/lipid interactions, however, are essential
to MP stability: Oligomeric MPs usually
feature subunit/subunit interactions in the
transmembrane region; the three-dimensional
(3D) structure of monomeric MPs, as well as
that of subunits, depends on protein/protein
interactions between their transmembrane
segments; and most MPs are extracted from
membranes along with bound lipids, which
stabilize them. Detergents compete with all of
these interactions, and micelles act as a “hydrophobic
sink” for molecules that, initially,
were associated with the MP under study.
Delipidation is one of the most, if not the
most, common causes of MP inactivation. The
destabilizing effect of diluting lipids, subunits,
and/or hydrophobic or amphipathic cofactors
among detergent micelles explains the fact
that, for a given detergent, working close to
the cmc, i.e., in the presence of few micelles,
will often improve the stability of MPs.