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At the heart of the chromosome: SMC proteins in action

Nature Reviews Molecular Cell Biology volume 7, pages 311–322 (2006)Cite this article

Key Points

  • Structural maintenance of chromosomes (SMC) proteins are highly conserved ATPases that have fundamental roles in higher-order chromosome organization and dynamics in organisms from bacteria to humans.

  • SMC dimers adopt a two-armed structure in which a central hinge domain connects long coiled-coil arms, each having an ATP-binding head domain at its distal end. The head domain of SMC proteins is structurally related to the ATP-binding cassette (ABC) domain of ABC transporters.

  • ATP binding and hydrolysis modulate the engagement and the disengagement of the head domains, respectively, and have an important role in regulating the dynamic interactions between SMC proteins and DNA.

  • The hinge domain is important for modulating the mechanochemical cycle of SMC proteins, implicating long-distance communication between the hinge and the head domains.

  • Condensin I has the capacity to introduce positive superhelical tension into DNA in an ATP-hydrolysis-dependent manner, possibly by organizing positive gyres or loops. A single-DNA-molecule assay reveals dynamic and reversible compaction of DNA supported by condensin I.

  • Cohesin might hold sister chromatids together by embracing two DNA duplexes within its ring-like structure, which is composed of SMC arms and a non-SMC 'kleisin' subunit.

  • SMC proteins might use a diverse array of intramolecular and intermolecular protein–protein interactions to tether, fold and manipulate the genome in an ATP-dependent manner.

Abstract

Structural maintenance of chromosomes (SMC) proteins are ubiquitous in organisms from bacteria to humans, and function as core components of the condensin and cohesin complexes in eukaryotes. SMC proteins adopt a V-shaped structure with two long arms, each of which has an ATP-binding head domain at the distal end. It is important to understand how these uniquely designed protein machines interact with DNA strands and how such interactions are modulated by the ATP-binding and -hydrolysis cycle. An emerging idea is that SMC proteins use a diverse array of intramolecular and intermolecular protein–protein interactions to actively fold, tether and manipulate DNA strands.

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Figure 1: The architecture of SMC proteins and SMC–protein complexes.
Figure 2: Structure and action of SMC protein subdomains.
Figure 3: Hypothetical actions of SMC proteins.
Figure 4: Comparison between SMC proteins and Rad50.
Figure 5: A gate-keeping role of the kleisin subunits in SMC protein actions.
Figure 6: A working model for the action of condensin.
Figure 7: Potential actions of cohesin.

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Acknowledgements

I thank the members of the Hirano laboratory for critically reading the manuscript. I am also grateful to many colleagues in the field for stimulating discussions. The work from the author's laboratory was supported by grants from the National Institutes of Health.

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    Tatsuya Hirano

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Glossary

Walker A and Walker B motifs

A pair of nucleotide-binding motifs that is commonly found in most, if not all, nucleotide-binding proteins.

Coiled-coil motif

A rod-like structural motif found in many proteins that is formed by two long α-helices twisted around each other. Parallel arrangements of the two helices are much more common than antiparallel arrangements.

Signature motif

(C motif). An amino-acid-sequence motif that is highly conserved among the ABC-ATPase superfamily, which includes ABC transporters, Rad50 and SMC proteins. This motif is not required for ATP binding but is essential for its hydrolysis.

ABC transporters

A large family of transmembrane ATPases that mediate the active translocation of a diverse range of small molecules in and out of cells and organelles. The functional unit of an ABC transporter is composed of two transmembrane domains and a pair of ATP-binding cassette (ABC) domains.

Rad50

The ATPase core subunit of the MRN (Mre11–Rad50–Nbs1) complex that has a crucial role in double-strand break repair. Rad50 shares many structural similarities with SMC proteins, including its ATP-binding head domains and its antiparallel coiled coils.

Transition-state mutation

A specific point mutation in the Walker B motif that stabilizes the engagement of two ABC domains by suppressing the hydrolysis of ATP molecules that are sandwiched between them.

Zinc-hook domain

A folding domain that is created at one end (apex) of the antiparallel coiled-coil arm of Rad50. A zinc ion bridges two hook domains and mediates their dimerization.

Atomic force microscopy

A scanning-microscopy technique that allows imaging of the surface of a sample at atomic resolution by measuring repulsive forces between a probing tip and the sample. It is possible to collect a series of time-resolved images under aqueous and physiological conditions.

Kleisins

A conserved family of proteins that directly interact with SMC protein dimers. Members of this family include the Scc1 subunit of cohesin, the CAP-H subunit of condensin and the ScpA subunit of the bacterial SMC complex.

Type I topoisomerase

A type of DNA topoisomerase that changes the topology of DNA by nicking and rejoining one strand of the DNA double helix.

Type II topoisomerase

A type of DNA topoisomerase that changes the topology of DNA by breaking and rejoining both strands of the DNA double helix.

Electron spectroscopic imaging

An electron-microscopy technique that provides both structural and analytical information on the basis of energy losses of an electron beam. The mapping of phosphorus allows the visualization of the path of DNA within a nucleoprotein complex. The technique is also used to measure the mass of the complex and to determine the stoichiometric relationship of protein and DNA components within the complex.

Magnetic tweezers

An experimental set-up that allows nanomanipulation of a single DNA molecule tethered to a paramagnetic bead. By measuring end-to-end extension of the DNA molecule to which a fixed force is applied, one can monitor the process of DNA compaction and decompaction in real time.

HEAT repeat

A ∼30 amino-acid-repeat motif that is found in a number of proteins with diverse functions. It was named after four proteins in which the repeat was originally detected (huntingtin, elongation factor 3, the regulatory A subunit of protein phosphatase 2A and TOR1).

Separase

A cysteine protease that promotes sister-chromatid separation at the onset of anaphase by cleaving the Scc1 subunit of cohesin.

Prereplication complex

A protein complex that assembles at replication origins from late mitosis through to the G1 phase. The assembly of this complex is a prerequisite for the initiation of DNA replication in S phase.

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Hirano, T. At the heart of the chromosome: SMC proteins in action. Nat Rev Mol Cell Biol 7, 311–322 (2006). https://doi.org/10.1038/nrm1909

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