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PubMed2001

Prokaryotic structural maintenance of chromosomes (SMC) proteins: distribution, phylogeny, and comparison with MukBs and additional prokaryotic and eukaryotic coiled-coil proteins.

Structural maintenance of chromosomes (SMC) proteins are known to be essential for chromosome segregation in some prokaryotes and in eukaryotes. A systematic search for the distribution of SMC proteins in prokaryotes with fully or partially sequenced genomes showed that they form a larger family than previously anticipated and raised the number of known prokaryotic homologs to 54. Secondary structure predictions revealed that the length of the globular N-terminal and C-terminal domains is extremely well conserved in contrast to the hinge domain and coiled-coil domains which are considerably shorter in several bacterial species. SMC proteins are present in all gram-positive bacteria and in nearly all archaea while they were found in less than half of the gram-negative bacteria. Phylogenetic analyses indicate that the SMC tree roughly resembles the 16S rRNA tree, but that cyanobacteria and Aquifex aeolicus obtained smc genes by lateral transfer from archaea. Fourteen out of 22 smc genes located in fully sequenced genomes seem to be co-transcribed with a second gene out of six different gene families, indicating that the deduced gene products might be involved in similar functions. The SMC proteins were compared with other prokaryotic proteins with long coiled-coil domains. The lengths of different protein domains and signature sequences allowed to differentiate SMCs, MukBs, which were found to be confined to gamma proteobacteria, and two subfamilies of COG 0419 including the SbcC nuclease from E. coli. A phylogenetic analysis was performed including the prokaryotic coiled-coil proteins as well as SMCs and Rad18 proteins from selected eukaryotes.

Amino Acid Motifs↗

PubMed1999

The Caulobacter crescentus smc gene is required for cell cycle progression and chromosome segregation.

The highly conserved SMC (Structural Maintenance of Chromosomes) proteins function in chromosome condensation, segregation, and other aspects of chromosome dynamics in both eukaryotes and prokaryotes. A null mutation in the Caulobacter crescentus smc gene is conditionally lethal and causes a cell cycle arrest at the predivisional cell stage. Chromosome segregation in wild-type and smc null mutant cells was examined by monitoring the intracellular localization of the replication origin and terminus by using fluorescence in situ hybridization. In wild-type cells, the origin is located at the flagellated pole of swarmer cells and, immediately after the initiation of DNA replication in stalked cells, one of the origins moves to the opposite pole, giving a bipolar localization of the origins. The terminus moves from the end of the swarmer cell opposite the origin to midcell. A subpopulation of the smc null mutant cells had mislocalized origins or termini, showing that the smc null mutation gives DNA segregation defects. Nucleoid morphology was also abnormal. Thus, we propose that the Caulobacter chromosomal origins have specific cellular addresses and that the SMC protein plays important roles in maintaining chromosome structure and in partitioning. The specific cell cycle arrest in the smc null mutant indicates the presence of a cell cycle checkpoint that senses perturbations in chromosome organization or segregation.

Bacterial Proteins↗

PubMed2002

Conserved disruptions in the predicted coiled-coil domains of eukaryotic SMC complexes: implications for structure and function.

The structural maintenance of chromosome (SMC) proteins are required for a number of essential nuclear processes, including those of chromosome condensation, chromatid cohesion, and DNA repair. Eukaryotic SMC proteins form heterodimers capable of binding DNA and possess a DNA-stimulated ATPase activity. They have a characteristic structure of terminal globular domains with two internal arms that are predicted to form a coiled-coil structure interspaced with a globular "hinge" domain. We report here that the predicted coiled-coil arms are disrupted at conserved sites in SMC proteins. These disruptions, which vary in length and sequence identity, abolish the otherwise symmetrical secondary structure of antiparallel SMC heterodimers and provide the first evidence for a possible functional orientation of eukaryotic SMC complexes. The retention of these breaks between evolutionarily distant, yet related, SMC members indicates that they may have a fundamental role in SMC heterodimer function.

Amino Acid Sequence↗

PubMed1989

Specific induction of 68 KD protein synthesis in rabbit smooth muscle cells by growth stimuli in platelets: comparison of intimal and medial SMC.

We examined the influence of growth stimuli in heat-treated platelet extract on specific protein synthesis in the early phase of the cell cycle prior to the initiation of DNA synthesis in cultured rabbit aortic smooth muscle cells (SMC). The extract preferentially stimulated the synthesis of a cytoplasmic protein with a molecular weight of 68000 (p68) and an isoelectric point of around 6.3. Stimulation of p68 synthesis occurred within 1 h after the addition of heat-treated platelet extract to growth-arrested and quiescent SMC, continued until 4 h after stimulation, and then returned to the baseline level. Actinomycin D preferentially inhibited p68 synthesis. In SMC prepared from atheromatous plaques from the aorta of hyperlipidemic rabbits (I-SMC), the amount of DNA synthesis and of p68 synthesis by heat-treated platelet extract were less than those of SMC prepared from normal media (M-SMC), suggesting that the decreased capacity for cell proliferation of I-SMC in response to heat-treated platelet extract was due to the down-regulation of signal transduction in the early G0/G1 phase of the cell cycle.

Animals↗

PubMed1996

[SMC proliferation and its distribution in autologous vein grafts].

SMC proliferation in intimal hyperplasia is a major cause of graft failure. We induced experimental jugular vein to aortic autograft in 120 Wistar rats, and analyzed the SMC proliferation and its distribution in the graft by flow cytometry (FCM) and immunohistochemistry of proliferating cellular nuclear antigen (PCNA) from 2 hours, 6 hours, 24 hours to 1 week, 2 weeks and 4 weeks. Although the number was not apparently increased in autologous vein graft at early stage, SMC proliferation had started. At 1 week after transplantation, the activity of SMC proliferation increased to a maximum, and returned to baseline level 4 weeks. At early stage, the distribution of SMC proliferation located in the media, but at middle stage, both intima and media all presented a relatively higher proliferative activity. The intima formation occurred by the migration of a large population and the proliferation of a relatively small subpopulation of SMC. Therefore, control of SMC proliferation, and migration of autologous vein grafts must be within two weeks after transplantation.

Animals↗

PubMed2006

The evolution of ATPase activity in SMC proteins.

The SMC (structural maintenance of chromosomes) proteins are a highly conserved and ubiquitous family of ATPases, found in nearly all living organisms examined, where they play crucial roles in transmission of the hereditary material. However, the extent to which efficient ATP hydrolysis is required for SMC function has been a matter of some debate. Here we investigate the potential functional significance of ATP binding and hydrolysis in different eukaryotic SMC proteins, both by comparing the conservation of conserved ATPase motifs and by exploring potential coevolution between associated domains. In this way, we have been able to account for the reduced requirement for ATPase activity in cohesin's SMC3 and demonstrate the greater apparent conservation requirements for such activity in condensin SMC proteins. Finally, we explore possible interactions between the SMC and non-SMC components of the condensin complex that are required for full condensin activity and may modulate ATPase activity in the holocomplex.

Adenosine Triphosphatases↗

PubMed2001

Crystal structure of the SMC head domain: an ABC ATPase with 900 residues antiparallel coiled-coil inserted.

SMC (structural maintenance of chromosomes) proteins are large coiled-coil proteins involved in chromosome condensation, sister chromatid cohesion, and DNA double-strand break processing. They share a conserved five-domain architecture with three globular domains separated by two long coiled-coil segments. The coiled-coil segments are antiparallel, bringing the N and C-terminal globular domains together. We have expressed a fusion protein of the N and C-terminal globular domains of Thermotoga maritima SMC in Escherichia coli by replacing the approximately 900 residue coiled-coil and hinge segment with a short peptide linker. The SMC head domain (SMChd) binds and condenses DNA in an ATP-dependent manner. Using selenomethionine-substituted protein and multiple anomalous dispersion phasing, we have solved the crystal structure of the SMChd to 3.1 A resolution. In the monoclinic crystal form, six SMChd molecules form two turns of a helix. The fold of SMChd is closely related to the ATP-binding cassette (ABC) ATPase family of proteins and Rad50, a member of the SMC family involved in DNA double-strand break repair. In SMChd, the ABC ATPase fold is formed by the N and C-terminal domains with the 900 residue coiled-coil and hinge segment inserted in the middle of the fold. The crystal structure of an SMChd confirms that the coiled-coil segments in SMC proteins are anti-parallel and shows how the N and C-terminal domains come together to form an ABC ATPase. Comparison to the structure of the MukB N-terminal domain demonstrates the close relationship between MukB and SMC proteins, and indicates a helix to strand conversion when N and C-terminal parts come together.

Adenosine Triphosphatases↗

PubMed2001

The structural maintenance of chromosomes (SMC) family of proteins in mammals.

Structural maintenance of chromosomes (SMC) family proteins play critical roles in chromosome structural changes. SMC proteins are known to be involved in two major chromosome structural organization events required for mitotic segregation of chromosomes: mitotic chromosome condensation and sister chromatid cohesion. In eukaryotes, two separate sets of SMC heterodimers form the cores of two distinct multiprotein complexes termed 'condensin' and 'cohesin', each specialized for condensation or cohesion, respectively. It is clear that both condensin and cohesin are conserved in mammals, including humans. The mammalian complexes demonstrate dynamic changes in intracellular distribution in a cell cycle-dependent manner. At any point in the cell cycle, the intracellular localization of the majority of mammalian cohesin and condensin appears to be complementary. Cohesin is associated with chromatin in interphase, while condensin is largely cytoplasmic. Similarly, in mitosis, cohesin is mostly excluded from chromosomes while condensin is distinctly bound to them. Cell cycle-dependent targeting of the two complexes appears to play a major role in regulating their cell cycle-specific activities, and how this redistribution is controlled is an area of active research. Finally, there is evidence that SMC proteins may be involved in DNA recombination and repair. This review focuses on what we have learned about SMC family proteins in humans and other mammalian species in comparison to those in lower eukaryotes. The authors present their own views with regard to some of the major outstanding questions surrounding the nature and functions of the SMC family of proteins.

Animals↗

PubMed1998

A Bacillus subtilis gene-encoding protein homologous to eukaryotic SMC motor protein is necessary for chromosome partition.

We have analysed the function of a gene of Bacillus subtilis, the product of which shows significant homology with eukaryotic SMC proteins essential for chromosome condensation and segregation. Two mutant strains were constructed; in one, the expression was under the control of the inducible spac promoter (conditional null) and, in the other, the gene was disrupted by insertion (disrupted null). Both could form colonies at 23 degree C but not at 37 degree C in the absence of the expression of the Smc protein, indicating that the B. subtilis smc gene was essential for cell growth at higher temperatures. Microscopic examination revealed the formation of anucleate and elongated cells and diffusion of nucleoids within the elongated cells in the disrupted null mutant grown at 23 degree C and in the conditional null mutant grown in low concentrations of IPTG at 37 degree C. In addition, immunofluorescence microscopy showed that subcellular localization of the SpoOJ partition protein was irregular in the smc disrupted null mutant, compared with bipolar localization in wild-type cells. These results indicate that the B. subtilis smc gene is essential for chromosome partition. The role of B. subtilis Smc protein in chromosome partition is discussed.

Bacillus subtilis↗

PubMed1998

ATP-dependent aggregation of single-stranded DNA by a bacterial SMC homodimer.

SMC (structural maintenance of chromosomes) proteins are putative ATPases that are highly conserved among Bacteria, Archaea and Eucarya. Eukaryotic SMC proteins are implicated in a diverse range of chromosome dynamics including chromosome condensation, dosage compensation and recombinational repair. In eukaryotes, two different SMC proteins form a heterodimer, which in turn acts as the core component of a large protein complex. Despite recent progress, no ATP-dependent activity has been found in individual SMC subunits. We report here the first biochemical characterization of a bacterial SMC protein from Bacillus subtilis. Unlike eukaryotic versions, the B.subtilis SMC protein (BsSMC) is a simple homodimer with no associated subunits. It binds preferentially to single-stranded DNA (ssDNA) and has a ssDNA-stimulated ATPase activity. In the presence of ATP, BsSMC forms large nucleoprotein aggregates in a ssDNA-specific manner. Proteolytic cleavage of BsSMC is changed upon binding to ATP and ssDNA. The energy-dependent aggregation of ssDNA might represent a primitive type of chromosome condensation that occurs during segregation of bacterial chromosomes.

Adenosine Triphosphatases↗

PubMed1996

SMC proteins constitute two subunits of the mammalian recombination complex RC-1.

Recombination protein complex RC-1, purified from calf thymus nuclear extracts, catalyzes cell-free DNA strand transfer and repair of gaps and deletions through DNA recombination. DNA polymerase E, DNA ligase III and a DNA structure-specific endonuclease co-purify with the five polypeptide complex. Here we describe the identification of two hitherto unknown subunits of RC-1. N-terminal amino acid sequences of the 160 and 130 kDa polypeptides display up to 100% identity to proteins of the structural maintenance of chromosomes (SMC) subfamilies 1 and 2. SMC proteins are involved in mitotic chromosome segregation and condensation, as well as in certain DNA repair pathways in fission (rad18 gene) and budding (RHC18 gene) yeast. The assignment was substantiated by immuno-cross-reactivity of the RC-1 subunits with polyclonal antibodies specific for Xenopus laevis SMC proteins. These antibodies, and polyclonal antibodies directed against the bovine 160 and 130 kDa polypeptides, named BSMC1 and BSMC2 (bovine SMC), inhibited RC-1-mediated DNA transfer, indicating that the SMC proteins are necessary components of the reaction. Two independent assays revealed DNA reannealing activity of RC-1, which resides in its BSMC subunits, thereby demonstrating a novel function of these proteins. To our knowledge, this is the first evidence for the association of mammalian SMC proteins with a multiprotein complex harboring, among others, DNA recombination, DNA ligase and DNA polymerase activities.

Adenosine Triphosphatases↗

PubMed2001

SMC proteins in bacteria: condensation motors for chromosome segregation?

SMC proteins are a ubiquitous protein family, present in almost all organisms so far analysed except for a few bacteria. They function in chromosome condensation, segregation, cohesion, and DNA recombination repair in eukaryotes, and can introduce positive writhe into DNA in vitro. SMC proteins and the structurally homologous MukB protein are unusual ATPases that form antiparallel dimers, with long coiled coil segments separating globular ends capable of binding DNA. Recently, SMC proteins have been shown to be essential for chromosome condensation, segregation and cell cycle progression in bacteria. Identification of a suppressor mutation for MukB in topoisomerase I in Escherichia coli suggests that SMC proteins are involved in negative DNA supercoiling in vivo, and by this means organize and compact chromosomes. A model is discussed in which bacterial SMC proteins act after an initial separation of replicated chromosome origins into the future daughter cell, separating sister chromatids by condensing replicated DNA strands within both cell halves. This would be analogous to a pulling of DNA strands into opposite cell halves by a condensation mechanism exerted at two specialised subregions in the cell.

Bacillus subtilis↗

PubMed1998

SMC proteins and chromosome structure.

The structure of chromosomes is largely determined by chromosome-associated proteins. Members of the SMC (structural maintenance of chromosomes) family play an important role in both prokaryotic and eukaryotic chromosome structure and dynamics. SMC proteins are involved in chromosome condensation, sister-chromatid cohesion, sex-chromosome dosage compensation, genetic recombination and DNA repair. There have been major advances recently in understanding the function of SMC proteins--including the identification of biochemical activities of SMC-containing protein complexes and the realization that individual SMC proteins might link seemingly unrelated aspects of chromosomal metabolism.

Animals↗

PubMed2005

FISH of supernumerary marker chromosomes (SMCs) identifies six diagnostically relevant intervals on chromosome 22q and a novel type of bisatellited SMC(22).

Supernumerary marker chromosomes (SMCs) are frequently found at pre- and postnatal cytogenetic diagnosis and require identification. A disproportionally large subset of SMCs is derived from the human chromosome 22 and confers tri- or tetrasomy for the cat eye chromosomal region (CECR, the proximal 2 Mb of chromosome 22q) and/or other segments of 22q. Using fluorescence in situ hybridization (FISH) and 15 different DNA probes, we studied nine unrelated patients with an SMC(22) that contained the CECR. Five patients showed the small (type I) cat eye syndrome (CES) chromosome and each one had the larger (type II) CES chromosome, small ring chromosome 22, der(22)t(11;22) extrachromosome, and a novel type of bisatellited SMC(22) with breakpoints outside the low-copy repeats (LCRs22). By size and morphology, the novel bisatellited SMC(22) resembled the typical (types I and II) CES chromosomes, but it might have been associated with the chromosome 22q duplication syndrome, not CES. This SMC included a marker from band 22q12.3 and conferred only one extra copy each of the 22 centromere, CECR, and common 22q11 deletion area. There has been no previous report of a bisatellited SMC(22) predicting the chromosome 22q duplication syndrome. Accounting for the cytogenetic resemblance to CES chromosomes but different makeup and prognosis, we propose naming this an atypical (type III) CES chromosome. In this study, we found six distinct intervals on 22q to be relevant for FISH diagnostics. We propose to characterize SMCs(22) using DNA probes corresponding to these intervals.

Abnormalities, Multiple↗

PubMed2004

Positive and negative regulation of SMC-DNA interactions by ATP and accessory proteins.

Structural maintenance of chromosomes (SMC) proteins are central regulators of higher-order chromosome dynamics from bacteria to humans. The Bacillus subtilis SMC (BsSMC) homodimer adopts a V-shaped structure with an ATP-binding catalytic domain at each end. We report here that two small proteins, ScpA and ScpB, associate with the catalytic domains of BsSMC in an ordered fashion and suppress its ATPase activity. When combined with a 'transition state' mutant of BsSMC that poorly hydrolyzes ATP, ScpA promotes stable engagement of two catalytic domains in an ATP-dependent manner. In solution, this occurs intramolecularly and closes the DNA-entry gate of an SMC dimer. ScpB further stabilizes this conformation and prevents BsSMC from binding to double-stranded DNA (dsDNA). In contrast, when the mutant BsSMC is first allowed to interact with dsDNA, subsequent addition of ScpA leads to assembly of large nucleoprotein complexes, possibly by stabilizing intermolecular engagement of the catalytic domains from different SMC dimers. We propose that the ATP-modulated engagement/disengagement cycle of SMC proteins plays both positive and negative roles in their dynamic interactions with dsDNA.

Adenosine Triphosphatases↗

PubMed1998

Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics.

The structural maintenance of chromosomes (SMC) family member proteins previously were shown to play a critical role in mitotic chromosome condensation and segregation in yeast and Xenopus. Other family members were demonstrated to be required for DNA repair in yeast and mammals. Although several different SMC proteins were identified in different organisms, little is known about the SMC proteins in humans. Here, we report the identification of four human SMC proteins that form two distinct heterodimeric complexes in the cell, the human chromosome-associated protein (hCAP)-C and hCAP-E protein complex (hCAP-C/hCAP-E), and the human SMC1 (hSMC1) and hSMC3 protein complex (hSMC1/hSMC3). The hCAP-C/hCAP-E complex is the human ortholog of the Xenopus chromosome-associated protein (XCAP)-C/XCAP-E complex required for mitotic chromosome condensation. We found that a second complex, hSMC1/hSMC3, is required for metaphase progression in mitotic cells. Punctate vs. diffuse distribution patterns of the hCAP-C/hCAP-E and hSMC1/hSMC3 complexes in the interphase nucleus indicate independent behaviors of the two complexes during the cell cycle. These results suggest that two distinct classes of SMC protein complexes are involved in different aspects of mitotic chromosome organization in human cells.

Amino Acid Sequence↗

PubMed1998

The symmetrical structure of structural maintenance of chromosomes (SMC) and MukB proteins: long, antiparallel coiled coils, folded at a flexible hinge.

Structural maintenance of chromosomes (SMC) proteins function in chromosome condensation and several other aspects of DNA processing. They are large proteins characterized by an NH2-terminal nucleotide triphosphate (NTP)-binding domain, two long segments of coiled coil separated by a hinge, and a COOH-terminal domain. Here, we have visualized by EM the SMC protein from Bacillus subtilis (BsSMC) and MukB from Escherichia coli, which we argue is a divergent SMC protein. Both BsSMC and MukB show two thin rods with globular domains at the ends emerging from the hinge. The hinge appears to be quite flexible: the arms can open up to 180 degrees, separating the terminal domains by 100 nm, or close to near 0 degrees, bringing the terminal globular domains together. A surprising observation is that the approximately 300-amino acid-long coiled coils are in an antiparallel arrangement. Known coiled coils are almost all parallel, and the longest antiparallel coiled coils known previously are 35-45 amino acids long. This antiparallel arrangement produces a symmetrical molecule with both an NH2- and a COOH-terminal domain at each end. The SMC molecule therefore has two complete and identical functional domains at the ends of the long arms. The bifunctional symmetry and a possible scissoring action at the hinge should provide unique biomechanical properties to the SMC proteins.

Bacterial Proteins↗

PubMedDate not supplied

Synthetically modified cellulose (SMC): a cellulosic hemodialysis membrane with minimized complement activation.

More dialysis treatments have been performed with cellulose based membranes than with any other material. As unmodified cellulose membranes activate the complement system, much effort has been directed toward the development of noncomplement activating cellulose membranes. One successful approach was the substitution of -OH groups in the cellobiose units of the cellulose molecule with tertiary amino groups, which resulted in a membrane called Hemophan. Synthetically modified cellulose (SMC) is a new hemodialysis membrane made by specific chemical modification whereby aromatic benzyl groups are covalently introduced into the cellulosic structure by ether bonds, creating hydrophobic domains within the overall hydrophilic cellulose surface: basic research investigations have shown that a characteristic hydrophobic-hydrophilic balance of surfaces is a prerequisite for improved hemocompatibility. Several cellulose modifications with aliphatic and aromatic groups were performed to achieve a membrane with the desired hemocompatibility profile; SMC, having hydrophobic benzyl groups, causes minimal activation of blood complement, coagulation, and cell activation systems. In vitro experiments with blood showed that C5a generation for SMC was reduced by 94% relative to Cuprophan (compared with 96% for polysulphone, a synthetic hemodialysis membrane). Activation of coagulation (formation of the thrombin-antithrombin III complex [TAT]) in a clinical study showed that SMC caused 16 ng/ml TAT generation compared with 36 ng/ml for polysulphone. SMC, a low-flux cellulosic dialysis membrane, thus combines the typically high diffusive performance characteristics of cellulosic membranes with excellent hemocompatibility, matching synthetic dialysis membranes.

Cellulose↗