GOLOV, GAVRILOV590
BIOCHEMISTRY (Moscow) Vol. 89 No. 4 2024
CONFORMATIONAL POLYMORPHISM
OF COHESIN COMPLEX
Activity of all proteins one way or another is asso-
ciated with ligand-dependent conformational changes.
SMC complexes demonstrate ability of radical confor-
mational rearrangements, which mediate their motor
activity.
Various microscopic techniques, X-ray crystallog-
raphy, as well as indirect approaches for elucidation of
structure such as Förster Resonance Energy Transfer
(FRET), chemical cross-linking, and analysis of stability
of DNA–protein complexes in various physicochemical
conditions facilitated discovery of a wide spectrum of
cohesin conformational states (Fig.3b)[3,4].
Entire variety of the known cohesin conforma-
tions could be described to a large degree by three
parameters: (1) engagement of head domains of the
two SMC subunits, (2) distance between the hinge and
head domains controlled by the degree of the elbow
bending, (3) distance between the arm coiled-coils of
two SMC subunit. For example, in both I-conformation
and folded conformation head domains are engaged,
and arm’s coiled coils interact along the entire length;
difference is in the fact that in the first conformation
arm domains are in the straightened state, while in
the second conformation – in the fully bended state.
O- and B-conformations differ from the previous pair
by the fact that interactions between the arm domains
are absent (Fig.3b).
Part of conformational rearrangements of cohes-
in is strictly coupled with ATP binding or hydrolysis,
while others occur spontaneously. It is likely though
that the direction of some spontaneous cohesin rear-
rangements could be controlled by the irreversible
processes of ATP binding and hydrolysis.
Dimerization of head domains and ATP hydro-
lysis. ATP binding induces tight interaction between
the two cohesin head domains, the so-called E-state
(engaged state) [9, 28, 47]. This short-lived structure
breaks down after ATP hydrolysis (Fig.3a). ATP hydro-
lysis is followed by the release of the products of hy-
drolysis and change in positioning of the head domain
relative to each. It was originally assumed that ATP
hydrolysis inevitably leads to a complete separation of
head domains in a structure known as an O-state (open
state). However, it has been later discovered that even
in the absence of ATP the structure called J-state (jux-
taposed state) can be formed in which two head do-
mains interact in such a way that the SGG-motifs of the
pair of SMC proteins are brought close to each other
[26, 48] (Fig. 3a). Considering that this interaction is
realized through the surfaces located at a relatively
large distance in the E-state, transitions from E-state
to J-state and back involve significant rotation of the
head domains relative to each other.
Additional conformational changes coupled
with binding and hydrolysis of ATP. ATP binding
and engagement of head domains in E-state is coupled
with several important conformational rearrangements:
local separation of arm domains, temporal dissocia-
tion of kleisin from SMC3, establishing of an addition-
al bridge between the two head domains formed by
NIPBL[25,44,49].
Coiled-coils of the arm domains that are adjacent
to the head domains are in fixed orientation relative
to each other in the J- and E-states. Despite the relative
flexibility of the arm domains, comparatively long re-
gions of the coiled coils adjacent to the head domains
are constitutively separated in the E-state [25, 44, 49].
At the same time, position of the head domains in the
J-state ensures close proximity of the coiled-coil re-
gions of SMC1 and SMC3[26, 48]. The available struc-
tural data indicate that the arm domains in the J-state
are in contact with each other over their entire length
(Fig.3a). Hence, while in the absence of ATP (in the so-
called apo-form) the arm domains could be either sep-
arated, or interact with each other to a certain degree,
binding of ATP results in separation of the coiled coils
at least in the regions directly adjacent to the head do-
mains.
During interaction of the head domains with each
other in the E- and J-state the united S-K-compartment
is divided into two compartments (SandK) confined by,
respectively, SMC dimer and kleisin subunit (Fig. 3a).
Depending on the nature of the interaction between
the head domains, the following subcompartments can
be distinguished: E-K, E-S, J-K, and J-S; due to the tight
contact between the coiled coils of the arm domain,
the latter does not have any opening.
Another change of cohesin conformation associat-
ed with ATP binding in the active center is short-term
opening of the so-called N-kleisin gates of the complex.
At the moment of formation of the E-state, the N-termi-
nal domain of RAD21 dissociates from its binding site
at the SMC3 subunit[47,49], which results in temporal
disruption of integrity of the E-K compartment.
ATP binding also causes changes in the pattern
of NIPBL interaction with other subunits. In addition
to its main binding site in the central part of kleisin,
NIPBL has additional ATP-regulated sites of interac-
tion with the SMC subunits. In the absence of ATP
NIPBL interacts with the dimer of hinge domains;
ATP binding results in dissociation of NIPBL from the
hinge domains and attachment to the head domain of
SMC3 [50]. This jump of NIPBL, likely, stimulates for-
mation of the E-state, in which NIPBL forms addition-
al contacts with the head domain of SMC1[25, 44,49].
Apair of conserved lysine residues in SMC3, K105/K106
(K112/K113– inSmc3 S. cerevisiae), plays an important
role in the interaction of NIPBL with the SMC3 head
domain, acetylation of these residues by acetyl trans-