熊本大学発生医学研究所／ P07-08 【英訳】Division of Developmental Regulation

Medical Cell Biology

Molecular chaperones
Focusing on the diverse functionalityof the AAA family of proteins
Molecular chaperones work to monitor and assist the life of proteins.
In particular, AAA proteins function to disaggregate protein aggregates,
and this family of proteins is the focus of Dr. Teru Ogura’s research.
Elucidating the mechanism of AAA proteins will help
our further understanding of neurodegenerative diseases.

AAA proteins mediate protein
recycling in cells
Proteins, which are vital to maintaining human life,
consist of genetically defined sequences of aminoacids that must fold into three-dimensional shapes
in order to perform their functions. Professor Ogura
says, “According to specific physical and chemicalrules, the linear sequence of amino acids determinesthe 3D structure, which is crucial for proper proteinfunction. However, proteins are very fragile andreadily denatured by heat and otherphysicochemical stresses, which cause them toaggregate with other proteins.” Here enters themolecular chaperone, the key subject of Dr. Ogura’s
research. Molecular chaperones monitor theformation of abnorma l or damaged proteins
resulting from aberrant cellular responses. They alsoa s si s t refold i ng of denat u re d protei n s a nddisaggregate proteins aggregates formed upon heatshock. “Literally, a chaperone means a caretaker, andmolecular chaperones are proteins that take care ofother proteins,” Dr. Ogura continues. “We focus on
the AAA (triple-A) family of proteins, which havemultiple functions distinct from those of other typesof molecu la r chaperones. A A A proteins a recharacterized by their ability to disaggregate proteinaggregates, such that they could theoretically unboileggs.” In addition, some AAA proteins degrade
unwanted proteins and reduce them into theirconstituent amino acids, which can then be used asbuilding blocks to make new proteins. In otherogura@gpo.kumamoto-u.ac.jp

ProfileObtained a Bachelor s degree from the Department of Biological Science,
Hiroshima University, then went on to receive a Ph.D. from theGraduate School of Science of Kyoto University.
After working as a researcher at the National Institute of Health, in 1985
Dr. Ogura became Assistant Professor at the Institute for
Medical Genetics at Kumamoto University Medical School. In 1987 he became
Senior Assistant Professor at the same institute, and Associate Professor in 1990.
1990 Research fellow, Edinburgh University, UK
2000 Associate Professor, Institute of Molecular Embryology and Genetics,
Kumamoto University
2002 Professor, IMEG.
2008-2009Director, IMEG

AAA family proteins are ubiquitous, found inorganisms from bacteria to humans. Similar sets ofAAA family proteins are present in a wide range ofspecies, from unicellular yeast to multicellularmammals. In order to elucidate the functions ofAAA family proteins, Dr. Ogura’s laboratory uses C.
elegans, one of the simplest multicellular organisms,
as well as unicellular yeast as model organisms.

Working towards elucidationand treatment ofneurodegenerative disorders
Recent resea rch e v idence shows t hat ma ny
neurodegenerative diseases including Alzheimer’sand Parkinson’s diseases arise from aggregation ofabnormal proteins. “These diseases are caused byamyloid fibrils, which are accumulation of misfolded
proteins, and molecular chaperones are capable ofdisassembling them,” Dr. Ogura says. “In patientswith neurodegenerative disorders, pathogenic
proteins tend to form amyloid fibrils and theactivities of molecular chaperones are altered.
However, no detailed underlying mechanisms havebeen clarified.” Depositions of abnormal proteins arecommonly found in Alzheimer’s and Parkinson’s
disease patients. Dr. Ogura emphasizes that researchmust be pursued from various perspectives, because

Membrane fusion,
protein translocation

AAA proteins

Endosomes
Vps4p/SKD1

NSF/Sec18p

Peroxisome biogenesis

Reconstitution of ER, Golgi,
and nuclear envelope

p97/VCP/Cdc48p

Cdc48p/VCP, smallminded/
MAC-1, CED-4/Apaf-1, katanin/MEI-1, spastin

Proteolysis

MotorsER-associated degradation

dyneinsproteasomal ATPases,
FtsH, ClpA, ClpX, HslU, Lon

DNA replication

Aggregation/disaggregation
and refolding of proteins

Orc, Cdc6p, Mcm, clamp-loaders
DnaA

DNA recombination, repair, andtranscriptional regulation

p97/VCP, Hsp104/ClpB, torsinA

Mitochondria

FtsHs, ClpC

red: AAA proteins
green: other AAA+ proteins

The pathogenesis of amyotrophic lateral sclerosis(ALS) may possibly involve an AAA protein, p97. “InALS patients, the activity of p97 is altered, although
its ATPase activity, which generates the energy forchaperone function, is not reduced. We do not evenknow yet whether we should activate or suppress thisAAA protein to prevent and treat ALS.”
Increasing attention is focused on the research on
molecular chaperones, which play a key role in thedevelopment of neurodegenerative diseases. Dr.
Ogura is investigating the mechanisms of molecularchaperones as a basis for understa nding
pathogenesis.

High-speed atomic force
microscopy accelerates
analytical research
Recently, Dr. Ogura’s laboratory has introduced astate-of-the-art analytical device—high-speed
atomic force microscope. “This apparatus canvisualize the movements of proteins and othermolecules. We are excited that this device hassignificantly advanced analysis of AAA proteinsproviding new data that were not available throughconventional approaches,” said Dr. Ogura, beamingwith hopes for the future.

Peroxisome disorders (Zellweger syndrome, neonatal adrenoleukodystrophy,
infantile Refsum disease)
Hereditary spastic paraplegia (AR-HSP)
Hereditary spastic paraplegia (AD-HSP)
Familial inclusion body myopathy with Paget disease of bone
and frontotemporal dementia (IBMPFD),
Amyotrophic lateral sclerosis (ALS)
Mitochondrial compex III deficiency, GRACILE syndrome, Björnstad syndrome
Spinocerebellar ataxia type 28 (SCA28), Spastic ataxia neuropathy syndrome

Paraplegin
Spastin
p97/VCPBCS1L
AFG3L2
AAA+ proteins
Torsin A
Axonemal dynein
Cytoplasmic dynein
Mysterin/RNF213
ORC1, ORC4, CDC6

Early onset torsin dystonia
Primary ciliary dyskinesia (PCD), Kartagener syndrome
Lissencephaly (Miller-Dieker lissencephaly)
Moyamoya disease
Meier-Gorlin syndrome

Structure of the AAA protein p97 and its binding toamyloid fibrils revealed by high-speed atomic force microscopy

RuvB, pontin, reptin, WRNIP1/Mgs1p, proteasomal ATPases,fidgetin, NtrC, PspF

Yta10p/Yta12p/paraplegin,
Yme1p, Msp1p, Bcs1p, Lon, ClpX

Chloroplasts

Pex1p, Pex6p

Pex1p, Pex6p

Mitosis, meiosis, apoptosis,
and microtubule dynamics

p97/VCP/Cdc48p, NSF

causative proteins differ by the types of disease.

Human diseases caused by mutations of AAA/AAA+ proteins

Various cellular functions of AAA proteins

Professor

Teru Ogura

words, these molecules scavenge and recycle protein
waste, serving as effective and efficient housekeepers
for the cell.

p97
amyloid fibrils

Maturation of ribosomes
Rix7p/NVL2, Rea1p, Drg1p

p97

10nm

100nm

References●Noi, K., Yamamoto, D., Nishikori, S., Arita-Morioka, K., Kato, T.,
Ando, T., and Ogura, T. High-speed atomic force microscopic
observation of ATP-dependent rotation of the AAA+ chaperone
p97. Structure 21,1992-2002,2013.
● Onit ake, A ., Yamanaka, K., Esak i, M., and Ogur a, T.
C a e n o r h a b d i t i s e l e g a n s f i d g et i n h o m o l o g F I G L-1, a
nuclear-localized AAA ATPase, binds to SUMO. J. Struct. Biol.
179, 143-151, 2012.
●Yamanaka, K., Sasagawa, Y., and Ogura, T. Recent advances in
p97/VCP/Cdc48 cellular functions. Biochim. Biophys. Acta 1823,
130-137, 2012.
●Nishikori, S., Esaki, M., Yamanaka, K., Sugimoto, S., and Ogura, T.
Positive cooperativity of the p97 AAA ATPase is critical foressential functions. J. Biol. Chem. 286, 15815-15820, 2011.

07Teaching Staff
Associate Professor

Assistant Professor

Kunitoshi Yamanaka

Masatoshi Esaki

My research is focused on the analysis of the functions
per fo r m ed by A A A fa mily chapero ne s, as well as themechanisms by which neurodegenerative diseases can occur
as a result of the malfunction of AAA chaperones. My approachto research is that there is always a need to come up with new
ideas in order to discover new things, and that determination iskey to achieving your research objectives.

Recently, my interest has been focused on how cellularorganelles such as mitochondria are constructed andmaintained. I would like to explain the phenomena observe by
microscopy in terms of the activity of molecules such asproteins. I am particularly interested in the functions of
Cdc48/p97, a cytosolic AAA chaperone.

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