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Life without Fur. Life without FUR: evolutionary reconstruction of transcriptional regulation of iron homeostasis in alpha-proteobacteria. Mikhail Gelfand Research and Training Center “Bioinformatics”, Institute for Information Transmission Problems, RAS

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Life without fur

Life without Fur


Life without fur

Life without FUR: evolutionary reconstruction of transcriptional regulation of iron homeostasis in alpha-proteobacteria

Mikhail Gelfand

Research and Training Center “Bioinformatics”, Institute for Information Transmission Problems, RAS

Russian-German Systems Biology Workshop

Moscow, February 27-29, 2008


Regulation of iron homeostasis the escherichia coli paradigm

Regulation of iron homeostasis (the Escherichia coli paradigm)

Iron:

  • essential cofactor (limiting in many environments)

  • dangerous at large concentrations

    FUR (Ferric Uptake Regulator: responds to iron):

  • synthesis of siderophores

  • transport (siderophores, heme, Fe2+, Fe3+)

  • storage

  • iron-dependent enzymes

  • synthesis of heme

  • synthesis of Fe-S clusters

    Similar in Bacillus subtilis


Regulation of iron homeostasis in proteobacteria

[+Fe]

[+Fe]

[- Fe]

[ Fe]

-

Irr

Irr

RirA

RirA

FeS

heme

degraded

2+

3+

S

i

d

e

r

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s

y

s

t

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m

s

FeS status

IscR

Fur

Fur

of cell

Fe

FeS

[- Fe]

[+Fe]

Regulation of iron homeostasis in α-proteobacteria

Experimental studies:

  • FUR/MUR: Bradyrhizobium, Rhizobium and Sinorhizobium

  • RirA (Rrf2 family): Rhizobium and Sinorhizobium

  • Irr (FUR family): Bradyrhizobium, Rhizobium and Brucella


Comparative genomics of regulatory systems

Comparative genomics of regulatory systems

  • Standard methods of comparative genomics:

    • similarity search by BLAST

    • Construction of phylogenetic trees to identify orthologs

    • General functional annotation by similarity

    • Assigning genes to functional subsystems using co-localization scores and phylogenetic profiles

  • Analysis of regulation:

    • Phylogenetic footprinting at short evolutionary distances: conserved motifs upstream of orthologs are likely sites

    • Consistency filtering at longer distances: true sites occur upstream of orthologs; false positives scattered at random


Distribution of transcription factors in genomes

Distribution of transcription factors in genomes


Fur mur branch of the fur family

Fur in g- and b- proteobacteria

Escherichia coli

: P0A9A9

sp|

ECOLI

Fur

Pseudomonas aeruginosa

: sp|Q03456

PSEAE

Fur in e- proteobacteria

Neisseria meningitidis

: sp|P0A0S7

NEIMA

HELPY

: sp|O25671

Helicobacter pylori

Fur in Firmicutes

BACSU

Bacillus subtilis

: P54574

sp|

SM mur

Sinorhizobium meliloti

MBNC03003179

Mesorhizobium

sp. BNC1

(I)

BQ fur2

Bartonella quintana

BMEI0375

Brucella melitensis

EE36 12413

sp. EE-36

Sulfitobacter

a

MBNC03003593

sp. BNC1

(II)

Mesorhizobium

RB2654 19538

HTCC2654

Rhodobacterales bacterium

AGR C 620

Agrobacterium tumefaciens

RHE_CH00378

Rhizobium

etli

RL mur

Rhizobium leguminosarum

Nham 0990

Mur

Nitrobacter hamburgensis

X14

in a-proteobacteria

Nwi 0013

Nitrobacter winogradskyi

RPA0450

Rhodopseudomonas palustris

Regulator of manganese

uptake genes (sit, mntH)

BJ fur

Bradyrhizobium japonicum

ROS217 18337

Roseovarius

sp.217

Jann 1799

Jannaschia

sp. CC51

SPO2477

Silicibacter pomeroyi

STM1w01000993

Silicibacter

sp. TM1040

MED193 22541

sp. MED193

Roseobacter

OB2597 02997

HTCC2597

Oceanicola batsensis

SKA53 03101

Loktanella vestfoldensis

SKA53

Rsph03000505

Rhodobacter sphaeroides

ISM 15430

Roseovarius nubinhibens

ISM

PU1002 04436

Pelagibacter ubique

HTCC1002

GOX0771

Gluconobacter oxydans

ZM01411

Zmomonas mobilis

y

Saro02001148

Novosphingobium aromaticivorans

a

Sala 1452

RB2256

Sphinopyxis alaskensis

Fur

ELI1325

in a-proteobacteria

Erythrobacter litoralis

OA2633 10204

Oceanicaulis alexandrii

HTCC2633

PB2503 04877

Parvularcula bermudensis

HTCC2503

Regulator of iron uptake

and metabolism genes

CC0057

Caulobacter crescentus

Rrub02001143

Rhodospirillum rubrum

Amb1009

(I)

Magnetospirillum magneticum

a

Amb4460

Magnetospirillum magneticum

(II)

Irr

a-proteobacteria

FUR/MUR branch of the FUR family


Fur and mur boxes

FUR and MUR boxes

Erythrobacter litoralis

Caulobacter crescentus

Novosphingobium aromaticivorans

Zymomonas mobilis

Oceanicaulis alexandrii

Sphinopyxis alaskensis

Rhodospirillum rubrum

Gluconobacter oxydans

Parvularcula bermudensis -

Magnetospirillum magneticum

Identified Mur-binding sites

Bacillus subtilis

Sequence logos for

known

Fur-binding sites

in Escherichia coli

and Bacillus subtilis

Mur

a

of - proteobacteria -

Escherichia coli


Irr branch of the fur family

Irr branch of the FUR family

Fur in g- and b- proteobacteria

Escherichia coli

ECOLI

: P0A9A9

sp|

Fur

Pseudomonas aeruginosa

: sp|Q03456

PSEAE

Neisseria meningitidis

: sp|P0A0S7

NEIMA

Fur in e- proteobacteria

HELPY

Helicobacter pylori

: sp|O25671

Fur in Firmicutes

BACSU

Bacillus subtilis

: P54574

sp|

a

a-proteobacteria

Mur /

Fur

AGR C 249

Agrobacterium tumefaciens

SM irr

Sinorhizobium meliloti

RHE CH00106

Rhizobium

etli

RL irr1

Rhizobium leguminosarum

(I)

RL irr2

Rhizobium leguminosarum

(II)

MLr5570

Mesorhizobium

loti

MBNC03003186

sp. BNC1

Mesorhizobium

BQ fur1

Bartonella quintana

BMEI1955

Irrin a-proteo-

bacteria

regulator of iron

homeostasis

Brucella melitensis

(I)

BMEI1563

Brucella melitensis

(II)

BJ blr1216

(II)

Bradyrhizobium japonicum

RB2654 182

Rhodobacterales bacterium

HTCC2654

SKA53 01126

Loktanella vestfoldensis

SKA53

ROS217 15500

Roseovarius

sp.217

ISM 00785

ISM

Roseovarius nubinhibens

OB2597 14726

Oceanicola batsensis

HTCC2597

Jann 1652

sp. CC51

Jannaschia

a

I

r

r

-

Rsph03001693

Rhodobacter sphaeroides

EE36 03493

Sulfitobacter

sp. EE-36

STM1w01001534

sp. TM1040

Silicibacter

MED193 17849

Roseobacter

sp. MED193

SPOA0445

Silicibacter pomeroyi

RC irr

Rhodobacter

capsulatus

RPA2339

(I)

Rhodopseudomonas palustris

RPA0424*

Rhodopseudomonas palustris

(II)

BJ irr*

(I)

Bradyrhizobium japonicum

Nwi 0035*

Nitrobacter winogradskyi

Nham 1013*

Nitrobacter hamburgensis

X14

PU1002 04361

Pelagibacter ubique

HTCC1002


Irr boxes

Irr boxes

Rhizobiaceae plus

Bradyrhizobiaceae

Rhodobacteriaceae

Rhodospirillales


Rira nsrr family rhizobiales

RirA/NsrR family (Rhizobiales)


Iscr family

IscR family


Summary regulation of genes in functional subsystems

Summary: regulation of genes in functional subsystems

Rhizobiales

Bradyrhizobiaceae

Rhodobacteriales

The Zoo (likely ancestral state)


Reconstruction of history

Reconstruction of history

Frequent co-regulation with Irr

Strict division of function with Irr

Appearance of theiron-Rhodo motif


Experimental validation

Experimental validation

  • RirA: sites and binding motifin Rhisobium legumisaurum(site-directed mutagenesis).Andy Johnston lab (University of East Anglia)

  • Microarray study if the Bradyrhizobium japonicum FUR– mutant: regulatory cascade FUR  irr:Mark O’Brian group (SUNY, Buffalo)


All logos and some very tempting hypotheses

2

All logos and Some Very Tempting Hypotheses:

  • Cross-recognition of FUR and IscR motifs in the ancestor.

  • When FUR had become MUR, and IscR had been lost in Rhizobiales, emerging RirA (from the Rrf2 family, with a rather different general consensus) took over their sites.

  • Iron-Rhodo boxes are recognized by IscR: directly testable

1

3


More stories

More stories

  • Regulation of methionine metabolism in Firmicutes (from S-boxes to T-boxes and transcriptional factors)

  • T-box regulon in Firmicutes (duplications, bursts, changes of specificity)

  • Regulation of respiration in gamma-proteobacteria (rewiring of regulatory cascades and shuffling of regulons)

  • Emerging global regulators in Enterobacteriaceae (how FruR has become CRA, and how duplicated RbsR has become PurR)


Open problems

Open problems

  • Regulatory systems are very flexible

    • easily lost

    • easily expanded (in particular, by duplication)

    • may change specificity

    • rapid turnover of regulatory sites

  • With more stories like these, we can start thinking about a general theory

    • catalog of elementary events; how frequent?

    • mechanisms (duplication, birth e.g. from enzymes, horizontal transfer)

    • conserved (regulon cores) and non-conserved (marginal regulon members) genes in relation to metabolic and functional subsystems/roles

    • (TF family-specific) protein-DNA recognition code

    • distribution of TF families in genomes; distribution of regulon sizes; etc.


Acknowledgements

Dmitry Rodionov (IITP, now at Burnham Institute, La Jolla, CA)

Andrew Johnston and Jonathan Todd(University of East Anglia, UK)

Howard Hughes Medical Institute

Russian Academy of Sciencesprogram “Molecular and Cellular Biology”

Acknowledgements


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