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2 Cren7: A Structural Homolog of Sul7

2 Cren7: A Structural Homolog of Sul7

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S.D. Bell and M.F. White



Fig. 10.2  Comparison of Cren7 and Sul7. The extended loop in Cren7 is shown in red and the

extra C-terminal a-helix of Sul7 is in blue. The figure was generated with Pymol using PDB

coordinates 2JTM (Cren7) and 1SSO (Sul7)



despite the complete lack of significant sequence similarity between the proteins,

they shared the same basic fold by having a b-barrel based SH3-like structure (Guo

et al. 2008). As can be seen in Fig. 10.2, the principal differences lie in the presence

of an extended loop in Cren7 (shown in red) and an extra C-terminal alpha-helix in

Sul7 (in blue). NMR studies suggested that DNA binding by Cren7 involves an

equivalent surface to that employed by Sul7, significantly the important hydrophobic intercalating residues (V26 and M29) in Sul7 have conservative replacements

(L28 and V36) in Cren7.



10.3 CC1

Examination of the genome sequences of organisms from the order Thermoproteales

revealed a surprising absence of clear homologs of single-stranded DNA binding

proteins (SSBs). Although of diverse sequence and composition across the three

domains of life, SSBs share a structural signature in the form of an OB fold. The

lack of this otherwise universal fold in Thermoproteales prompted a biochemical

search for candidate ssDNA binding activities in organisms of this order. This led

to the identification of CC1, a small basic protein of primarily beta-sheet organisation (Luo et al. 2007). The protein has the capacity to bind with high cooperativity

and with nearly identical affinities to either ssDNA or dsDNA (Luo et al. 2007) and

a binding site size of approximately 6 bp per monomer (Hardy and Martin 2008).

The ability to bind tightly to ssDNA differentiates CC1 from Sso7d, which binds

ssDNA very poorly (Hardy and Martin 2008). While CC1 is restricted to the

Thermoproteales and Aeropyrum pernix, the beta-sheet rich structure is reminiscent

of both Sul7 and Cren7, suggesting that despite low amino acid sequence similarity,

there may turn out to be structural homologies between CC1 and these proteins. We

have therefore grouped these proteins together in Fig. 10.7.



10  Archaeal Chromatin Organization



209



10.4 MC1

MC1 is an abundant DNA binding protein in species of methanogenic euryarchaea

of the order Methanosarcinales. It is additionally found in some halophilic euryarchaea such as as Haloquadratum, Halobacterium, Haloarcula and Natromonas.

While single genes for MC1 are found in the halophiles, Methanosarcina species

have two MC1 genes, encoding proteins that are about 90% identical. As with many

chromatin-associated proteins, MC1 proteins are small (87–94 amino acids) and

highly basic. They bind DNA non-cooperatively and each monomer covers about

10–11 bp. Binding introduces a sharp bend of about 120° in DNA (Le Cam et al.

1999). In common with some bacterial chromatin proteins and eukaryotic HMG

proteins, MC1 shows some preference for binding to aberrant DNA structures, such

as mini-circles and four-way junctions (Teyssier et al. 1996; Toulme et al. 1995).

The structure of Methanosarcina thermophila MC1 revealed that it had a novel fold

with one a helix and five b-strands arranged in two antiparallel sheets that fold to

form a b-barrel like structure (Paquet et al. 2004) (Fig. 10.3). The b-barrel shares

topological similarities to that of the Sul7/Cren7 structures, although the loops connecting the b-strands vary significantly in size.

The precise DNA-binding mode employed by MC1 remains unclear, however, it

is possible that it may resemble that of Sul7. Thus, the b-barrel fold employed by

a number of archaeal chromatin proteins may be reflective of an ancestral DNAorganising domain that has been embellished in a number of archaeal lineages.

Interestingly, Methanosarcina thermophila encodes a SET-domain protein. SET

domains have methyltransferase activity and play pivotal roles in the differential

methylation of eukaryotic chromatin proteins. Biochemical studies revealed that

the Methanosarcina SET domain protein could methylate MC1, however, the

physiological relevance of this in vitro observation remains unclear (Manzur and

Zhou 2005).



Fig. 10.3  The structure of MC1. Comparison with Fig. 10.2 reveals the similar b-barrel folds of

MC1, Cren7 and Sul7. The figure was generated with Pymol using PDB coordinates 1T23



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S.D. Bell and M.F. White



10.5 Sac10a

Sac10a was isolated from S. acidocaldarius extracts as an abundant DNA binding

protein that has the capacity to introduce supercoiling and bring together two

duplexes into interwound structures. It has been estimated to be highly abundant,

reaching levels similar to those of Sul7. DNA binding studies have revealed a modest

sequence preference for A/T rich DNA (Edmondson et al. 2004). Given this modest

degree of sequence preference of the protein, it is currently unclear whether the

Sul10a protein is a true general chromatin protein, or a transcription factor associated

with specific genetic loci. The protein is found in a range of both cren- and euryarchaea. Essentially nothing is known about the physiological role of this protein,

beyond the observation that its abundance appears to reduce as Sulfolobus cultures

enter stationary phase (Edmondson et al. 2004). Biochemical and structural studies

have revealed the protein to be a homodimer. The protein homodimerises via a long

anti-parallel coiled coil generating an extended structure (Kahsai et al. 2005). The

linear extremities of the dimer are formed by winged-helix DNA binding domains,

one contributed by each monomer (Fig. 10.4).



10.6 Alba

Identified at the same time as Sac10a, Alba (Sac10b or Sso10b) has been the

subject of a number of biochemical and structural studies. Alba is found in both

euryarchaeal and crenarchaeal kingdoms as well as in a variety of eukaryotes,

ranging from Trypanosomes to Man (Bell et  al. 2002). Several archaeal species,

including members of the Sulfolobus genus, encode two Alba family members,

Alba1 and Alba2 (Jelinska et al. 2005). In Sulfolobus, Alba1 comprises about 4%

of total cell protein, while Alba2 is about 20-fold less abundant (Jelinska et  al.

2005). The proteins function as dimers and structures of homodimers of Alba1

from a number of archaea have been determined. In addition the structure of a heterodimer of Sulfolobus Alba1–Alba2 has also been solved (Jelinska et  al. 2005;

Wardleworth et  al. 2002). Interestingly the preferred higher order form of Alba2

appears to be in a heterodimer with Alba1. The structures reveal that Alba forms a

twofold symmetric structure with a central alpha-helical rich core from which two



Fig. 10.4  Structure of the Sac10a homo-dimer. The figure was generated with Pymol using PDB

coordinates 1R7J



10  Archaeal Chromatin Organization



211



Fig. 10.5  Comparison of Alba1 homodimer and Alba1-2 heterodimer (Alba1 in green, Alba2 in

magenta). The site of in vivo acetylation (K16) in Alba1 is shown as spheres. The figure was generated with Pymol using PDB coordinates 1HOX (Alba1 homodimer) and 2BKY (heterodimer)



b-hairpin wings protrude (Fig.  10.5). The fold of the N-terminal region of Alba

resembles the DNA binding fold of DNaseI and also bears similarity to the RNA

binding fold of translation factor IF3.

Alba appears to be a reasonably promiscuous nucleic acid binding protein with

a preference for binding double stranded nucleic acids. Both DNA and RNA can be

bound in vitro and in vivo (Guo et al. 2003; Marsh et al. 2005). Interaction of Alba1

with dsDNA constrains negative supercoils and electron microscopy studies have

revealed that it coats DNA in a filamentous structure (Jelinska et  al. 2005; Lurz

et al. 1986). The nature of these filaments varies with changing Alba:DNA ratios.

At 6 bp/Alba1 dimer, extended filaments are observed in which all the DNA is

coated. At lower ratios (12 bp/dimer) tangled structures are observed in which

loops of uncoated DNA are seen to extrude from stem-like structures in which two

duplexes appear to be interwound by Alba-DNA filaments. The behaviour of

Alba1.Alba2 heterodimers was similar to Alba1 homodimers at 12 bp/dimer.

However, at higher protein concentrations the heterodimers resulted in the formation of novel, branched structures in which protein coated loops extruded out from

a central condensed mass of protein and DNA (Jelinska et al. 2005). The ability of

Alba to form these filament structures may explain its ability to raise the melting

temperature of DNA significantly (Richard et al. 2004). This suggests, that in addition to organising chromatin, Alba may also act as a thermo-protectant for both

DNA and RNA in the cell.

The crystallographic studies reveal a possible basis for the distinct behaviours of

the homo- and heterodimers. Examination of the crystal lattices of Alba1 homodimers reveals that Alba1 has the propensity to form filament structures via end-toend association of homodimers involving a strikingly well conserved interface.

Significantly, this site is poorly conserved in the Alba2 protein, suggesting it may

act as a filament breaker (Jelinska et al. 2005).

Native Alba1 from S. solfataricus was found to have lower DNA binding affinity

that recombinant material purified from Escherichia coli. Mass spectrometry

revealed that the native material possessed two sites of acetylation, one at the



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Fig. 10.6  Structure of a homodimer of M. fervidus HmfB and the pseudo-dimeric histone from

M. kandleri (HmkA). The peptide linking the two histone folds is highlighted in blue. The figure

was generated with Pymol using PDB coordinates 1A7W (HMfB) and 1F1E (HMkA)



N-terminus and the other at lysine 16 (Bell et al. 2002). Furthermore, mutagenesis

of the K16 in the recombinant protein to either glutamate or alanine resulted in

lowered DNA binding affinity. Thus it appears that acetylation of Alba may modulate its DNA binding affinity. The structure of Alba1 reveals that K16 is positioned

in the alpha-helical bundle of Alba, in a position where it is likely to make direct

contacts with DNA; removal of the positive charge of the lysine side chain upon

acetylation would therefore be predicted to interfere with DNA binding.

It was particularly notable, therefore, that native Alba1 was found to co-immunopurify

with Sulfolobus Sir2 – a homolog of the eukaryotic NAD-dependent Sir2 protein

deacetylases. In eukaryotes, the Sir2 protein plays a number of significant roles in

regulating the activity of proteins by reversible acetylation. Importantly, physiological substrates for eukaryotic Sir2 proteins include the histone proteins. Treatment

of native Alba1 with Sir2 enhanced its DNA binding affinity and this could be

detected by the enhanced repressive potential of Sir2-treated native Alba1 in

in vitro transcription assays (Bell et al. 2002). Studies of bacterial Sir2 homologs

had revealed that they play a key role in the regulation of acetyl coA synthetase

(ACS) in partnership with an acetyltransferase, Pat (Starai et al. 2002; Starai and

Escalante-Semerena 2004). Interestingly in both Alba1 and bacterial ACS, the

acetylated lysine is preceded by a glycine. Furthermore, archaea encoded a short

protein homologous to the acetyltransferase domain of Pat. Experiments with the

Sulfolobus Pat homolog (ssPat), revealed that this protein was able to acetylate

Alba1 and did so specifically on K16. Furthermore, this led to a reduction in the

DNA binding affinity of Alba1 in vitro (Marsh et al. 2005). Thus, it appears likely

that the Pat-Sir2 partnership, that in bacteria is involved in modulating the key



10  Archaeal Chromatin Organization



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metabolic enzyme, acetyl CoA synthetase, has been co-opted in Sulfolobus to form

a primitive form of chromatin regulation machinery. It is tempting to speculate that

this may allow coupling of the global control of chromatin organisation (and thus

DNA replication and gene transcription) to changes in the energy flux and metabolic status of cells.



10.7 Archaeal Histones

In 1990, studies of the DNA binding proteins of Methanothermus fervidus revealed

that this species encoded bona fide orthologs of eukaryotic histone proteins

(Sandman et al. 1990). The principal unit of DNA compaction in eukaryotes is the

histone octamer. This contains two copies each of histone H2A, H2B, H3 and H4.

The assembly of the octamer and its interaction with DNA to form a nucleosome

core particle is an ordered and chaperoned event in eukaryotes. First a basic tetramer

of 2 copies of each of H3 and H4 forms a tetramer, this then has a one copy of H2A

and H2B added either side of the H3/H4 tetramer to form the histone octamer. The

archaeal histones most closely resemble eukaryotic H3 and H4 (Reeve et al. 2004).

All four eukaryotic histones have a common core fold, the “histone fold” containing

three alpha helices that are separated by two short b-loops. In eukaryotes, tails are

found both N-and C-terminal of the core histone fold. The tail sequences show considerable conservation within each histone type and contain a great many sites of

post-translational modification. There is currently no evidence that any archaeal

histones are subject to any post-translational modifications. Furthermore, most

archaeal histones lack significant tails, at most they possess a few extra residues,

beyond the core histone fold. A few archaeal histones do have short C-terminal tails

(typically of less than 25 residues). These may play regulatory roles as deletion of

one such tail (in Methanocaldococcus jannaschii MJ1647) appears to stimulate

DNA binding by this protein (Li et al. 2000). While the precise physiological role of

the histones remains poorly understood, a body of data has been amassed on the

biochemistry of the proteins. In general, histone fold-containing proteins are insoluble

as monomers but stable as dimers. Many archaea possess multiple histone homologs

and these have been shown to be capable of both homo-dimeric and hetero-dimeric

interactions. In two archaea, Methanopyrus kandleri and Halobacterium salinarum,

unusual histones are observed which contain two histone folds within one polypeptide (Fahrner et al. 2001); (Sandman and Reeve 2006). Thus, these proteins can be

viewed as obligate pseudo-heterodimers.

Many archaea encode multiple histone genes and in Thermococcus zilligii,

Methanococcus voltae and M. fervidus, differential expression of distinct histone

homologs during culture growth was observed leading to speculation that the differential abundance of the homo and heterodimeric forms may modulate the nature

of nucleoid organisation in different growth conditions (Dinger et  al. 2000;

Sandman et al. 1994).

When binding to DNA, archaeal histones form a tetramer or dimer of dimers

analogous to the eukayotic (H3/H4)2 tetrasome (Reeve et al. 2004). Mutations in



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S.D. Bell and M.F. White



the dimer–dimer interface impair the ability of the histones to bind DNA. The

­histone tetramer binds approximately 90 bp of dsDNA, wrapping it around the

surface of the histone tetramer. Not surprisingly, in vitro substrate selection studies

revealed that archaeal histones, like their eukaryotic counterparts, show elevated

binding to intrinsically curved DNA sequences (Bailey et al. 2002).



10.8 Phylogenetic Distribution of Archaeal Chromatin Proteins

The chromatin protein distribution shown in Fig. 10.7 emphasises that there is no

“universal” archaeal chromatin protein and, furthermore, suggests that displacement of one chromatin protein by another appears to have occurred several times in



Crenarchaea



Alba



CC1

Cren7

Sul7



Sulfolobus

Ignicoccus

Aeropyrum

Pyrobaculum

Thermofilum

Cenarchaeum

Korarchaeum

Nanoarchaeum



HU



Thermoplasma

Picrophilus

Archaeoglobus

Pyrococcus

Methanocaldococcus



MC1



Methanosarcina

Halobacterium



Euryarchaea



histone



Fig.  10.7  Phylogenetic distribution of the major archaeal chromatin proteins. Representative

archaeal species are indicated. Cenarcheum is a representative of the recently proposed

Thaumarchaeal phylum



10  Archaeal Chromatin Organization



215



the course of evolution. The clearest example is in the Thermoplasmatales, where

the archaeal histone has been lost, possibly due to lateral gene transfer of a bacterial

gene encoding the chromatin protein HU. Similarly, it is tempting to postulate that

Alba has been displaced by MC1 in the Methanosarcinas and halophiles. It is not

possible to state definitively whether the Cren7-like family has displaced histones

in most crenarchaea, or conversely that histone genes have been laterally transferred into a few crenarchaea such as Thermophilum pendens, resulting in loss of

Cren7. What is clear is that all sequenced archaeal genomes encode at least two

different chromatin proteins that presumably collaborate to organise and compact

the genome (eg. the Alba and Cren7 families in Sulfolobales; Alba and HU in

Thermoplasmatales; Histones and Alba in Pyrococcales etc.). A similar situation

exists in the bacteria, and as in the bacteria no single archaeal chromatin protein

may be essential for cell viability, as deletion of either Alba or histone genes has

been demonstrated in Methanococcus voltae (Heinicke et al. 2004). Thus, archaeal

chromatin presents a curious blend of eukaryotic and bacterial features. With the

continuing improvements in archaeal genetic systems it is anticipated that there will

be significant and rapid progress in elucidating the precise roles of archaeal chromatin proteins in shaping the organisation of the nucleoid in these fascinating

organisms.



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Chapter 11



The Topology and Organization

of Eukaryotic Chromatin

Andrew Travers and Georgi Muskhelishvili



Abstract  In all organisms DNA is maintained in a highly compacted state complexed with abundant basic proteins. The extent of this compaction can range from

~1,000-fold in the bacterial nucleoid to ~10,000-fold in eukaryotic metaphase

chromosomes. In addition to the necessity for compaction the genetic specification

function of DNA also requires that the appropriate encoded information be accessible for transcription. The dual requirements of compaction and selective accessibility imply that the complex of DNA and abundant basic proteins, defined here

generally as chromatin, must possess a high degree of structural organisation and

that the regulation of transcription at the level of the gene may involve substantial

structural transitions. In this article we summarise the current understanding of the

organisation of eukaryotic chromatin and discuss the extent to which the organisational principles are also apparent in prokaryotic chromatin.

Keywords  Chromatin organisation • DNA structure • nucleosomes • 30 nm fibre

• nucleoid-associated proteins



11.1 Introduction

In all organisms DNA is maintained in a highly compacted state complexed with

abundant basic proteins. The extent of this compaction can range from ~1,000-fold

in the bacterial nucleoid to ~10,000-fold in eukaryotic metaphase chromosomes. In

addition to the necessity for compaction the genetic specification function of DNA

also requires that the appropriate encoded information be accessible for transcription.

A. Travers ()

Fondation Pierre-Gilles de Gennes pour la Recherche, c/o LBPA,

École Normale Supérieure de Cachan, 94235, Cachan, France;

MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK

e-mail: aat@mrc-lmb.cam.ac.uk

G. Muskhelishvili

Jacobs University, Campus Ring 1, D-28759, Bremen, Germany



R.T. Dame and C.J. Dorman (eds.), Bacterial Chromatin,

DOI 10.1007/978-90-481-3473-1_11, © Springer Science+Business Media B.V. 2010



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