Science - USA (2019-01-18)

INSIGHTS | PERSPECTIVES

sciencemag.org SCIENCE

GRAPHIC: V. ALTOUNIAN/

SCIENCE

By Ulrich Brandt

A

ll expressions of life ultimately de-
pend on energy derived from redox
chemistry and photosynthesis. On
page 257 of this issue, Schuller et al.
( 1 ) report the structure of photosyn-
thetic complex I at atomic resolu-
tion. The authors have analyzed how the
distinct NADH [reduced form of oxidized
nicotinamide adenine dinucleotide (NAD+)]
dehydrogenase subunit S (NdhS) facilitates
electron transfer from ferredoxin, thereby
establishing efficient cyclic electron flow
around photosystem I. The findings add an
important piece to the puzzle of deciphering
the enigmatic mechanisms at work in the
remarkable molecular machines of the com-
plex I superfamily encompassing photosyn-
thetic and respiratory complex I, as well as
proton pumping hydrogenases. In combina-
tion with high resolution struc-
tures of respiratory complex I
from bacteria ( 2 ), mitochondria
( 3 – 5 ), and membrane bound hy-
drogenase ( 6 ), it is now possible
to trace the modular evolution
and functional adaptations of
the complex I superfamily at the
atomic level.
Evolutionary studies suggest
that the metabolism of the last
universal common ancestor re-
lied on the reduction of carbon
dioxide and nitrogen by hydro-
gen and hydrogen sulfide, as-
sisted by transition metals such
as iron, nickel, and molybdenum
( 7 ). This basal redox chemistry
provided the building blocks
for organic molecules, nucleic
acids, and proteins. The integra-
tion of photosynthesis into this
primordial power supply tapped
sunlight as an unlimited energy
source. With the advent of water
splitting photosynthesis and ter-
minal oxidases, oxygen became
the major player in the overall
cycle of biological energy. Thus,
going back to the origin of life,

biological electron transfer, respiration, and

photosynthesis were closely intertwined and

accompanied by the modular unfolding of

the complex I superfamily of redox enzymes.

The module common to all members of

the complex I superfamily is provided by

soluble [NiFe] hydrogenases ( 8 ). These hy-

drogenases have a [NiFe] active site and

catalyze the reversible conversion of hydro-

gen to protons and electrons. They also fea-

ture a chain of three iron-sulfur clusters and

harbor a substrate binding site for hydrogen

(H-module) or plasto-, mena-, or ubiquinone

(Q-module). Although the active site evolved

to bind chemically different substrates while

concomitantly losing the [NiFe] center—

from soluble hydrogenase to mitochondrial

complex I—both the sequence and struc-

ture of nearby domains are conserved ( 3 , 4 ,

9 , 10 ). Hydrogenases acquired a membrane

anchor and a proton-translocating module

(PI) from the multiple resistance and pH

(Mrp)–type sodium-proton antiporter, yield-

ing the energy-converting hydrogenase (Ech)

that energetically connects electron transfer

between ferredoxin and hydrogen to proton

translocation across a membrane. The Mrp

transporters also trace back to the last uni-

versal common ancestor, in which they are

proposed to play a role in establishing the so-

dium gradient across the plasma membrane

to drive primordial adenosine triphosphate

(ATP)–synthase ( 7 ). The structure of the hy-

drogen gas–evolving membrane-bound hy-

drogenase (Mbh) revealed that it retained

the sodium translocating module (S) of Mrp

and expanded the PI-module by adding three

additional subunits. This resulted in a com-

position very similar to that of the proximal

proton pumping (PP) module of complex I ( 6 ).

Instead of the S-module, photosynthetic and

respiratory complex I retained the second

proton-translocating module of

Mrp (PII), duplicating it to form

the distal proton pumping (PD)

module. Strikingly, however,

as compared with Mbh, the PP-

module is rotated 180° in the

membrane plane in complex I,

probably retaining the relative

topology of the modules in Mrp.

This is particularly remarkable

because irrespective of the orien-

tation of the PP-module, proton

pumping is driven by the redox

chemistry taking place in the ho-

mologous Q- or H-module.

The membrane-bound hy-

drogenases of the complex I su-

perfamily mostly use ferredoxin

as the electron donor or accep-

tor for the H-module. Ferredoxin

also reduces the Q-module of

photosynthetic complex I, pass-

ing on electrons from photo-

system I. However, as shown

by Schuller et al., an additional

NdhS subunit (see the figure,

module F) greatly facilitates

recognition and binding of the

redox protein, thereby optimiz-

ing cyclic electron transfer. Re-

spiratory complex I turned into

a NADH-dehydrogenase by cap-

turing its electron input module

from the NAD+ -reducing hy-

drogenase. The H-module of this

STRUCTURAL BIOLOGY

Adaptations of an ancient modular machine

Mechanism of energy conversion is conserved in the complex I superfamily

Radboud Institute for Molecular Life Sciences,
Department of Pediatrics, Radboud University
Medical Center, Geert Grooteplein-Zuid 10,
Route 772, 6525 GA Nijmegen, Netherlands.
Email: [email protected]

Soluble

hydrogenase

Energy-converting

hydrogenase

Photosynthetic

complex I

Membrane bound

hydrogenase

NAD+-reducing

hydrogenase

Mrp sodium–proton

antiporters

Respiratory

complex I

Complex I superfamily

H

N

H

H

PD

PII PI S

Q

PD PP

N

H

S PP

Q

PP

F

PD

H

Q

PI-II

F

Proton translocating I and II

Ferredoxin binding

PP

Modules

Quinone binding

SSodium translocating

Hydrogen binding

PDDistal proton translocating

Proximal proton translocating

230 18 JANUARY 2019 • VOL 363 ISSUE 6424

Modular design of the

complex I superfamily

The complex I superfamily evolved

from different soluble hydrogenases

and Mrp sodium–proton antiporters

by combining ancient modules dating

back to the last universal common

ancestor. Its members have adapted

to use diverse substrates, yet several

functional domains are conserved.

Published by AAAS

on January 17, 2019^

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