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Figure legends
Figure 1. Relationship between the penta-EF-hand (PEF) protein family and the calpain
family in mammals. Classical (typical) calpain sequences contain the PEF domain and
the calpain type β-sandwich domain (CBSW) in addition to the cysteine protease core
domain (CysPc), which is further divided into two subdomains named PC1 (containing
a catalytic Cys residue) and PC2 (containing catalytic His and Asn residues).
Conventional calpains (μ-calpain and m-calpain) are comprised of each catalytic large
subunit (designated CAPN1 for μ-calpain or CAPN2 for m-calpain) and a common
regulatory small subunit (CAPNS1). Non-classical (atypical) calpain sequences lack the
PEF domain but contain additional domains or motifs [calcium-binding C2 domain,
microtubule-interacting
and
trafficking
(MIT)
domain,
Zinc
finger
(ZnF),
SOL-homology domain (SOH), and circularly permutated globin domain (cpGB) split
by the calmodulin-binding IQ motif]. Calpain-3 (CAPN3), specifically expressed in
skeletal muscles, has distinct sequences: N-terminal sequence (NS), insertion sequence
1 (IS1), and insertion sequence 2 (IS2). Calpain-7 (CAPN7) is an ortholog of fungal
PalB. PEF proteins are classified into two groups based on similarity of the first
EF-hand (EF1) sequences [15].
Figure 2. Schematic structures of ALG-2-interacting proteins reported in the literature.
The human or murine ALG-2-interacting proteins are classified into five groups for
convenience sake based on functional properties: (a) ESCRT system, (b) ER-to-Golgi
vesicular transport, (c) RNA processing, (d) protein kinases, and (e) miscellaneous.
Underlined proteins have been studied in the author’s group. Red boxes and thick violet
bars indicate Pro-rich regions (PRRs) and determined ALG-2-binding regions,
respectively. PTP, phosphotyrosine phosphatase; UEV, ubiquitin E2 variant; CC,
coiled-coil; SB, steadiness box; LC1, light chain 1; CID, C-terminal domain
(CTD)-interacting domain; ZnF, zinc finger; RRM, RNA recognition motif; Ig-like C2,
24
immunoglobulin-like constant domain type 2; ANK, ankyrin; TM, transmembrane; C2,
Protein Kinase C C2-domain-like Ca2+-binding domain; vWFA, von Willebrand factor
A.
Figure 3. PEF-binding motifs and 3D structures. (a) Three types of Pro-rich
ALG-2-binding
motifs
(ABMs).
Residues
conserved
among
the
identified
ALG-2-interacting proteins in each type of ABM are indicated in red, and residues
compatible with the type 2 motif at the Ω position are indicated in violet. [PΦ], Pro or
hydrophobic; [FW], Phe or Trp; Ω, large side chain; x, variable. (b) Overall 3D structure
of the complex between ALG-2 (homodimer) and ALIX peptides (indicated by magenta
arrows) is shown by a cartoon in rainbow colors (from blue in the N-terminal region to
red in the C-terminal region) using the 3D presentation software PyMOL and Protein
Data Bank (PDB) code 2ZNE. (c) Overall 3D structure of the complex between ALG-2
and Sec31A peptides. PDB code 3WXA. A side view (left panel) and a 90°-rotated
bottom view (right panel). (d) Schematic representation of a three-binding-site model of
calpain inhibition by calpastatin. Among the three conserved regions of the four
repeated domains of calpastatin, region B binds the protease domain and inhibits the
proteolytic activity of calpain. Regions A and C bind the PEF domains of the large
subunit (L-PEF) and the small subunit (S-PEF), respectively. (e) Amino acid sequences
of regions A and C of human calpastatin. Conserved (identical or similar) residues are
highlighted in light green for region A and in cyan for region C. Conserved residues
between the two regions are marked with asterisks, where high conservation is indicated
by bold face. (f) Overall 3D structure of the complex between rat m-calpain and
calpastatin domain 1 (PDB code 3DF0). The PEF domains and the calpastatin peptide
are shown by cartoon models in rainbow colors and in magenta, respectively. Other
calpain domains are shown by surface representation in pale colors.
Figure 4. Schematic diagram of calpain-7 actions on ESCRT-mediated EGF receptor
25
downregulation in the endosome-to-lysosome pathway. Calpain-7 (CAPN7) is recruited
to endosomes after stimulation of cells with epidermal growth factor (EGF) and
regulates downregulation of the ubiquitinated and endocytosed EGF receptor (EGFR).
Calpain-7 interacts via the tandemly repeated microtubule-interacting and trafficking
(MIT) domains with a subset of ESCRT-III subunits (CHMP proteins) and related
proteins that contain MIT-interacting motifs (MIMs). ALG-2 interacts with IST1, a
CHMP-like protein, in a Ca2+-dependent manner at the Met-Pro repeat (MP) region.
Endogenous substrates of calpain-7 have not been identified yet. Fungal and yeast
orthologs of calpain-7 cleave ALIX-homolog-interacting transcription factors in
association with ESCRT-III proteins. VPS4 (isoforms A and B) and spastin, meiotic
clade AAA ATPases containing MIT domains, disassemble ESCRT-III polymers and
microtubules, respectively [101,102]. CHMP, charged multivesicular body protein;
MTBD, microtubule binding domain; MVB, multivesicular body; Ub, ubiquitin.
26
Table 1. Distribution of penta-EF-hand (PEF) proteins, classical calpains and calpain-7 orthologs in eukaryotes
PEF proteins and calpains
PEF proteins
ALG-2/PEF 1)
peflin
Protist
Plant
Yeast
Fungus
Nematode
Fly
Mammal
classical calpains
Large subunit
Small subunit
sorcin
grancalcin
CAPN7
calpain-7/PalB/Rim13 2)
1)
Names of homologs are different among organisms, and functions of mammalian ALG-2 are different from
those of lower eukaryotic homologs.
2)
PalB (fungus) and Rim13 (yeast) have similar functions of processing transcription factors involved in alkaline
adaptation system, but the physiological substrate of mammalian CAPN7 (calpain-7) has not been identified yet.
peflin
284
sorcin
198
grancalcin
217
CAPNS2
248
CAPNS1
268
CysPc
CAPN3
PalB subfamily
calpain family
CAPN1, 2, 8, 9,
11, 12, 13, 14
NS
PC1
PC2
HN
IS1
CBSW
669
- 739
IS2
821
C2
CAPN5, 6
640, 641
MIT MIT
CAPN7
813
CAPN10
672
ZnF
SOH
CAPN15
CAPN16
Figure 1
1086
cpGB
PC2’
1667
IQ
PEF protein family
191
Group II
calpain small subunits
ALG-2
Group I
PEF
ESCRT system
Bro1
ALIX
PRR
868
PTP
PEST
1636
HD-PTP
UEV
CC SB
390
TSG101
VPS37C
355
285
VPS37B
364
IST1
D Protein kinases
Tyr kinase
Ig-like C2 repeat
1356
VEGFR2
kinase
ER-to-Golgi vesicular transport
Sec31A
kinase
505
1220
245
E Miscellaneous
LC1
2464
MAP1B
648
Raf1
WD40 repeat
MISSL
kinase
1374
Death
1430
ANK repeat
DAPK1
annexin repeat
Annexin A11
Ask1
RNA processing
PLSCR3
Annexin A7
Tubby-like
295
TM
Scotin
240
annexin repeat
488
region C
770
PATL1
G-patch
916
CID
CHERP
ZnF RRM
RBM22
Figure 2
420
580
MCOLN1
C2 C2
HEBP2
SARAF
205
CPNE4
339
vWFA
557
ALG-2-binding motif (ABM)
Type 1: PPYPxxxxYP
ALIX
798-AQGPPYPTYPGYPGYC-813
PLSCR3
13-SPPPPYPVTPGYPEPA- 28
CHERP
562-FERPPYPHRFDYPQGD-577
ALIX
peptide
Type 2: [PΦ]Px[PΦ]G[FW]Ω
Sec31A
834-HGENPPPPGFIMHGNV-849
PLSCR3
40-AQVPAPAPGFALFPSP- 55
PATL1
306-GQMLPPAPGFRAFFSA-321
SARAF
219-NSAGPPPPGFKSEFTG-234
PDB 2ZNE
Type 3: MP repeats
IST1
226-GTVPMPMPMPMPSANT-241
811-GYCQMPMPMGYNPYAY-826
ALIX
Sec31A peptide
PDB 3WXA
E Regions A and C of calpastatin
calpain
CysPc
1A
2A
3A
4A
L-PEF
CBSW
PC1 PC2
S-PEF
calpastatin
1C
2C
3C
4C
ABC ABC ABC ABC
153-MDAALDDLIDTLGG
287-SDQALEALSASLGT
430-PDDAVEALADSLGK
567-LDDALDKLSDSLGQ
** ****** *
228-PDDAIDALSSDFTC
365-ESELIDELSEDFDR
508-EDFLLDALSEDFSG
647-DQDPIDALSGDLDS
L-PEF
calpain
L-PEF
calpastatin
region A
S-PEF
S-PEF
calpastatin
region C
CBSW
PC1
calpastatin
region A
PDB 3DF0
Figure 3
calpastatin
region C
PC2
calpain
CysPc
calpastatin
region B
MTBD
CHMP1
spastin
MP
IST1
VPS4
ALG-2
Ca2+
microtubule severing
Key
proteolysis
: MIT
: MIM
: interaction
calpain-7
Bro1
PRR
signaling &
modification?
ALIX
ALG-2
Ca2+
(CHMP4)
ESCRT-I
ESCRT-0 ESCRT-II
EGFR
Ub
Endosome
Figure 4
ESCRT-III
disassembly
inward
budding
Lysosome
degradation
ESCRT-III
(CHMPs)
MVB
...
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