Table 3.
Comparison of Nav1.5 and Nav1.4 channel associated/regulatory proteins and corresponding binding sites.
| Region | Nav1.4/1.5 interacting proteins | Nav1.5 | Nav1.4 | % aa sequence similarity | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Binding sites | Mutations | Pathologies | References | Binding sites | Mutations | Pathol-ogies | References | |||
| DI S5–S6 loop | Navβ1 | Equivalent sequence: (278–388) HKC—GKI (111 aa) |
R282H, V294M, G319S R282H G292S K317N L325R G351V T353I D356N R367C, M369K R367H R376H R376H L276Q, H278D, R282C, V300I, L315P, K317- T320N, E346X, G351D R367C, R367L, M369K W374G, G386R, G386E |
BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS BrS |
Priori et al., 2002 Itoh et al., 2005a Niimura et al., 2004 Yi et al., 2003 Keller et al., 2005 Vatta et al., 2002 Pfahnl et al., 2007 Makiyama et al., 2005 Smits et al., 2002 Takehara et al., 2004 Frustaci et al., 2005 Rossenbacker et al., 2004 Kapplinger et al., 2010 Kapplinger et al., 2010 Kapplinger et al., 2010 Kapplinger et al., 2010 Kapplinger et al., 2010 |
(278–422) QKC–GKT (145 aa) (Makita et al., 1996 |
63.1% | |||
| ID I-II | Dynamitin |
(417–444) EEQ—KKE (28 aa) Chatin et al., 2014 |
E428K, H445D, L461V E439K E446K E462K |
AF BrS DCM LQT3 |
Darbar et al., 2008 Kapplinger et al., 2010 McNair et al., 2011 Tester et al., 2005 |
Equivalent sequence: (451–478) AEQ–KKH (28 aa) |
85.7% | |||
| 14-3-3 |
(417–467) EEQ—PLA (51 aa) Allouis et al., 2006 |
Equivalent sequence: (451–482) AEQ—EAD (32aa) |
66.7% | |||||||
| CaMKII |
(417–711) EEQ–GVK (295 aa) Ashpole et al., 2012 |
Equivalent sequence: (451–572) AEQ—IIH (122 aa) |
87.1% in ID first 31 aa (418–449:452–484) 80.0% in ID last 60 aa (655–714:517–575) |
|||||||
| ID II-III | Ankyrin-G |
(1047–1055) VPIAVAESD (9 aa) Mohler et al., 2004 |
S941N R971C A997S T1069M R1023H |
LQT3 LQT3 LQT3 LQT3 BrS |
Schwartz et al., 2000 Tester et al., 2005 Ackerman et al., 2001 Tester et al., 2005 Frustaci et al., 2005 |
(925–933) VPIASEESD (9 aa) Lemaillet et al., 2003 |
S804N | SCM | Fournier et al., 2006 | 77.8% |
| MOG1 |
(940–1200) SSF—CYH (261 aa) Wu et al., 2008 |
E1053K, R965C D1055G, R965H, A997T S1079Y, A1113V, S1140T D1114N A1180V R1193Q |
BrS BrS BrS LQT3 DCM LQT3 |
Priori et al., 2002 Kapplinger et al., 2010 Kapplinger et al., 2010 Splawski et al., 2000 Ge et al., 2008 Wang et al., 2004 |
Equivalent sequence: (803–1026) SSF—CFK (224 aa) |
50.2% | ||||
| ID III-IV | α-Actinin-2 |
(1471–1523) DNF—IFD (53 aa) Ziane et al., 2010 |
G1481E F1486L Y1494N M1498T L1501V |
LQT3 LQT3 BrS LQT3 LQT3 |
Tester et al., 2005 Wang et al., 2007 Tian et al., 2007 Napolitano et al., 2005 Splawski et al., 2000 |
Equivalent sequence: (1296–1348) DNF—VYD (53 aa) |
N1297K G1306E G1306E G1306E |
SNDM SCM SNEL PC |
Gay et al., 2008 Mitrovic et al., 1995 Lion-Francois et al., 2010 Fleischhauer et al., 1998 |
94.5% |
| Calmodulin |
(1471–1523) DNF—IFD (53 aa) Potet et al., 2009 |
L1501V, I1521K G1502S DQKP 1507-1509 R1512W F1520L |
BrS BrS LQT3 BrS DCM |
Kapplinger et al., 2010 Smits et al., 2005 Keller et al., 2003 Deschênes et al., 2000 McNair et al., 2011 |
Equivalent sequence: (1296–1348) DNF—VYD (53 aa) |
G1306V T1313M T1313A |
PC PC PC |
Plassart et al., 1994 Fukudome et al., 2003 Bouhours et al., 2004 |
94.5% | |
| DIV S5-S6 loop | Navβ1 | Equivalent sequence: (1720–1748) ILN—AVG (29 aa) |
G1712S | BrS | Kapplinger et al., 2010 |
(1545–1574) ILN—SIG (30 aa) Makita et al., 1996 |
90.1% | |||
| C-ter | FGF12/13 |
(1784–1864) EPL—LGE (81 aa) Liu et al., 2003 Wang et al., 2011 |
E1784K E1784K E1784K S1787N D1790G 1795insD 1795insD Y1795C L1825P R1826H Q1832E, V1861I D1840G |
BrS LQT3 L/B LQT3 LQT3 L/B LQT3 L/B LQT3 LQT3 BrS LQT3 |
Priori et al., 2002 Splawski et al., 2000 Makita et al., 2008 Splawski et al., 2000 An et al., 1998 Bezzina et al., 1999 van Langen et al., 2003 Rivolta et al., 2001 Makita et al., 2002 Ackerman et al., 2001 Kapplinger et al., 2010 Benhorin et al., 1998 |
Equivalent sequence: (1610–1690) EPL—LGD (81 aa) |
95.1% | |||
| C-ter | Calmodulin |
(1908–1919) IQ-motif IQRAFRRHLLQR (12aa) Tan et al., 2002 Young and Caldwell, 2005 |
Q1909R R1913H |
LQT3 LQT3 |
Tester et al., 2005 Napolitano et al., 2005 |
(1734–1745) IQRAYRRHLLQR (12aa) Young and Caldwell, 2005 |
100.0% | |||
| Nedd4-2 |
(1974-1980) PY-motif PPSYDSV (7 aa) van Bemmelen et al., 2004 |
No homology | No homology | |||||||
| Syntrophin |
(2014–2016) SIV (3 aa) Ou et al., 2003 |
(1834–1836) SLV (3 aa) Gee et al., 1998 |
100.0% | |||||||
| PTPH1 |
(2014–2016) SIV (3 aa) Jespersen et al., 2006 |
Equivalent sequence: (1834–1836) SLV (3 aa) |
100.0% | |||||||
| SAP97 |
(2014–2016) SIV (3 aa) Petitprez et al., 2011 |
Equivalent sequence: (1834–1836) SLV (3 aa) |
100.0% | |||||||
For each channel the identified binding site (in bold) and the equivalent sequence on the channel counterpart are presented. The % amino acid sequence similarities between Nav1.5 (NCBI Reference Sequence NP_932173.1) and Nav1.4 (NP_000325.4) channels were estimated using the following website: http://www.ch.embnet.org/software/LALIGN_form.html. Nav1.4 interaction with ankyrin is only suggested by chimeric constructs, it remains to be studied with full length proteins (Lemaillet et al., 2003). It is noticeable that Nedd4-2 consensus binding site “PPSYD(E in Nav1.8)S(R in Nav1.1)” is present in all human Nav channels except Nav1.4. Single amino acid mutations identified in human disease in each binding site are reported. DI to DIV, domains I to IV; DI(S5-S6) and DIV(S5-S6), extracellular connecting loops between S5 and S6 intramembrane segments in domains I and IV; ID, intracellular interdomains; N-ter and C-ter, N- and C-terminus ends; BrS, Brugada Syndrome; AF, Atrial Fibrillation; LQT3, Type 3 long QT syndrome; L/B, Overlap of LQT3 and BrS; DCM, Dilated Cardiomyopathy; SCM, Sodium Channel Myotonia; SNEL, Sporadic Neonatal Episodic Laryngospasm; PC, Paramyotonia Congenita; SNDM, Severe neonatal Non-Dystrophic Myotonia.