Structural basis for specific recognition of K6-linked polyubiqu
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Article
Structural basis for specific recognition of K6-linked
polyubiquitin chains by the TAB2 NZF domain
Yanjun Li,
1
Kei Okatsu,
2
Shuya Fukai,
2
and Yusuke Sato
3,4,
*
1
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan;
2
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan;
3
Center for Research on Green Sustainable
Chemistry and
4
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori, Japan
ABSTRACT TAK1-binding protein 2 (TAB2) has generally been considered to bind specifically to K63-linked polyubiquitin
chains via its C-terminal Npl4 zinc-finger (NZF) domain. However, a recent study showed that the NZF domain of TAB2
(TAB2-NZF) could also interact with K6-linked polyubiquitin chains. Here, we report the crystal structure of TAB2-NZF in com-
plex with K6-linked diubiquitin (K6-Ub
2
) at 1.99-A
˚
resolution. TAB2-NZF simultaneously interacts with the distal and proximal
ubiquitin moieties of K6-Ub
2
. By comparing the structures of TAB2-NZF in complex with K6-Ub
2
and with K63-linked diubiquitin
(K63-Ub
2
), we reveal that the binding mechanism of TAB2-NZF with K6-Ub
2
is similar to that with K63-Ub
2
, except for the flexible
C-terminal region of the distal ubiquitin. Therefore, we conclude that the C-terminal flexibility of the distal ubiquitin contributes to
the dual specificity of TAB2-NZF toward K6- and K63-linked ubiquitin chains. This study provides important insights into the func-
tions of K6-linked ubiquitin chains, which are currently unclear.
INTRODUCTION
Ubiquitin, a 76-amino-acid protein, is highly conserved in
eukaryotic cells (1). Protein ubiquitination is an important
post-translational modification that regulates various bio-
logical processes such as DNA repair, transcription, protein
degradation, and inflammatory signaling (2). Ubiquitin is
typically conjugated to the amino group of the substrate
lysine residue via its C-terminal carboxyl group (3). The
amino groups of the N-terminal methionine residue and
seven lysine residues of ubiquitin can be covalently bonded
to the C-terminus of another ubiquitin to form eight types of
polyubiquitin chains (M1, K6, K11, K27, K29, K33, K48,
and K63 chains). Polyubiquitin chains regulate different
cellular functions depending on their linkage types (2,4).
Among the eight types of polyubiquitin chains, the func-
tions of K48, K63, and M1 chains have been studied more
extensively than the other chains. For example, K48 chains
act as the primary targeting signal for proteasomal degrada-
tion, whereas M1 and K63 chains have proteolysis-indepen-
dent functions (2,4,5).
For instance, the formation of M1 and K63 chains is
induced in the cytosol when cells are stimulated by inflam-
matory cytokines such as tumor necrosis factor-a or inter-
leukin-1b (6,7). K63 chai ns are required in the activation of
the nuclear factor kB(NF-kB) and c-Jun N-terminal kinase
(JNK) signaling pathways, which regulate cell proliferation,
apoptosis, inflammation, and immune responses (8–10). M1
chains recruit the inhibitors of NF-kB kinase (IKK) complex
that contains IKKa,IKKb, and NF-kB essential modulator,
and K63 chains recruit the transforming growth factor-b-
activated kinase 1 (TAK1) complex that contains TAK1,
TAK1 binding protein (TAB) 1, TAB2, and its homolog,
TAB3. TAK1 directly phosphorylates IKKb and mitogen-
activated protein kinase kinases to stimulate the NF-kB and
JNK pathways, respectively (11–13). It was suggested that
Submitted March 28, 2021, and accepted for publication June 29, 2021.
*Correspondence: yusato@tottori-u.ac.jp
Editor: Jill Trewhella.
SIGNIFICANCE Ubiquitin can form a covalently linked polymer via its N-terminal methionine or seven lysine residues to
form eight types of polyubiquitin chains (M1, K6, K11, K27, K29, K33, K48, and K63 chains, respectively). Among these,
K63 chains bind to the NZF domain of TAB2 to activate the TAK1 complex, which plays essential roles in cell proliferation,
apoptosis, inflammation, and immune responses. On the other hand, a recent study showed that K6 chains also bind to the
NZF domain of TAB2, although there has been no report that K6 chains are involved in the activation of the TAK1 complex.
Our structural analyses reveal how the NZF domain of TAB2 has dual specificity toward K6 and K63 chains.
Biophysical Journal 120, 3355–3362, August 17, 2021 3355
https://doi.org/10.1016/j.bpj.2021.06.037
Ó 2021 Biophysical Society.
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