20 4 2008 8 Chinese Bulletin of Life Sciences Vol. 20, No. 4 Aug., 2008 10040374(2008)04056613 1 100101 2 100086 ( ) (I II III IV) I/II III III IV c V ATP ( ) ATP I II III IV NADH c c Q244 Q518.3 A Structure of mitochondrial respiratory membrane protein complexes SUN Fei 1 *, ZHOU Qiangjun 1, SUN Ji 1, ZHAI Yujia 1, RAO Zihe 2 (1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; 2 TsinghuaNankaiIBP Joint Research Group for Structural Biology, Tsinghua University, Beijing 100086, China) Abstract: As the important energy factory of eukaryotic cells, mitochondrion is the place for cellular respiration that includes citric acid cycle and oxidative phosphorylation process (OXPHOS). The OXPHOS electron transfer chain (mitochondrial respiration chain) is located on the inner membrane of mitochondrion and comprising of four large transmembrane protein complexes (mitochondrial respiratory Complex I, II, III and IV) as well as ubiquinone between Complex I/II and III and cytochrome c between Complex III and IV. The function of mitochondrial respiration chain is biological oxidation which is coupled with phosphorylation by ATP synthesis enzyme (ATPase, called Complex V) and then complete OXPHOS producing energy molecule ATP. Structural researches on those membrane protein complexes in mitochondrial respiration chain are very important for understanding the mechanisms of electron transfer and energy transformation. Here we reviewed the structural studies of mitochondrial respiratory complexes respectively as well as the structural research progresses on their respiratory supra complexes. Key words: mitochondrial respiratory complexes; structural biology; NADH: ubiquinone oxidoreductase; succinate:ubiquinone oxidoreductase; cytochrome c reductase; cytochrome c oxidase 20080701 973 (2006CB806506) * Email feisun@ibp.ac.cn
567 Krebs (matrix) A CO 2 ATP NADH FADH 2 ( ) NADH FADH 2 (mitochondrial intermembrane space, IMS) ATP (ATPase) ATPase (adenosine triphosphate, ATP) ADP ( ATP ) ( I II III IV) I/II III III IV c ( 1) (prosthetic group) NAD + (NADH) FMN (FMNH2) ubiquinone/ Q( ubiquinoil/qh2) FAD(FADH 2 ) (heme a heme a3 heme b heme c heme c1)[ ] (ironsulfur center FeS) Cu ([2Fe2S]) ([4Fe4S]) ([3Fe4S]) ( ) 14Å [1] ( 2) I NADH FMN 1M NADH 2 Q 4 (negative ) (positive ) NADH FMN FeS Q NADH+H + +4H + (N)+Q NAD + +QH 2 +4H + (P) FAD b (cyt. b556) (succinate) Q 1 IIIV I II I III IV UQ: Q; cyt. c: c; succinate: ; fumarate:
568 2 succinate FAD FeS Q succinate+q fumarate( )+ QH 2 c(cyt. c) b(b562 b566) c1 Q c 4 2cyt.c ( ) + QH 2 +2H + (N) 2cyt.c ( )+Q+4 H + (P) c (a1 a3) (Cu B ) (Cu A ) a3 Cu B FeCu (a3cu B ) [2Fe2S] c 2 2 cyt c Cu A heme a1 a3cu B O 2 4cyt.c ( )+8 H + (N)+O 2 4cyt.c ( )+4 H + (P)+2H 2 O I III IV ATPase ATP ATPase (uncoupling protein, UCP) UCP I II III IV I II III IV X (I III 2 I III 2 IV III 2 IV 2 ) UCP 1 I(Complex I) NADH I( I EC1.6.5.3) NADH (dihydronicotinamide adenine dinucleotideubiquinone oxidoreductase) NADH I 45 [2,3] 1 (flavinmononucleotide, FMN) 8 1M 7 ND1 ND6 ND4L [4,5] I I(NDH1) 13~14 550k I [6] [7] I NADH I L ( 3A) [810]
569 3 I A I (peripheral part) (connection part) (transmembrane part) I (accessory subunits) B Thermus thermophilus I C( Å) D I Q II X III X IV Q I 13/14 3 (peripheral part) 7 (transmembrane part) 3/4 (connection part) I (accessory subunits) I I Leonard [11] Neurospora crassa I I I L [12] 1997 I 35Å [13] 1998 I 34Å I L I [10] Grigorieff I I 22Å I L [8] I I L I 2002 Friedrich L I [14] Sanzonov [15] 2006 Radermacher [16] Yarrowia lipolytica I I 16.5Å I 2007 Baranova [17] NDH1
570 NDH1 8Å Q Radermacher Baranova I I 2005 Science Hinchliffe Sazanov Thermus thermophilus I 9 ( 3C) I 8 [18] 2006 Science 3.3Å [19] ( 3B) 14Å NADH FMN N3 N1b N4 N5 N6a N6b N2 Q(N ) Nqo3 N7 ( ) I 8 N1a FMN [20] I I I I ( 3D) (1) Q III Q / [21] (2) IV FMN N2 [22] Q [23,24] (3) F ATP [25] Ca 2+ ATP [26] 2 II(Complex II) II( II EC1.3.5.1) (succinate : ubiquinone oxidoreductase SQR) (succinate) (fumarate) Q FAD [2Fe2S] [4Fe4S] [3Fe4S] (heme b) Q II (SQR ) (heterodimmer) A B (flavoprotein, FP) (Iron Sulfur binding protein, IP) FAD [2Fe2S] [4Fe4S] [3Fe4S] [27] A E II C 4 II A: II FP IP CybL CybS FAD [2Fe2S] [4Fe4S] [3Fe4S] FP (FAD ) Q CybS B: II C: ( Å)
571 [28] 4A II FP IP CybL CybS 125k SQR Iverson [29] 1999 QFR( eqfr D ) 3.3Å 11 Lancaster [30] Wolinella succinogenes QFR( wqfr B ) 2.2Å 2003 Iwata SQR 2.6Å [31] II SQR II II II III II SQR 20 2 (TTFA) 5,6 2 N 1,4 3 ( carboxanilide) II [32,33] II II 2005 II 2.4Å ( 4B) 3 (3NPA) TTFA 3. 5Å [34,35] II II SQR SQR II II (pheochromocytoma headandneck paraganglioma ) Berry II [36] 2.1Å 3NPA II II II 3NPA (3.5Å) [37] II / / 2000 Lancaster [38] wqfr wqfre66q 3.1Å 66 2001 wqfr 3. 1Å capping 301 QFR [39] 2002 Iverson [40] eqfr eqfr C 29 2006 Iwata Atpenin A5 SQR II [41] Huang II II 1 2 [42] 2 TTFA II 2 II TTFA 3.5Å TTFA 2 [34] Berry II TTFA TTFA [37] II Succinate + FAD Fumarate + FADH 2 2e FADH FAD + 2H + 2e + 2 N [2Fe2S] [4Fe 4S] [3Fe 4S]( heme) 2e
572 2e + Q + 2H QH + N 2 H + N ( 4C) Q [3Fe 4S] heme [3Fe4S] [3Fe4S] Q heme II heme (EPR) II II II 3 III(Complex III) c ( III, EC1.10.2.2) c (cytochrome c reductase) bc1 I II III c III 11 240k III b( b562/b H b566/b L ) c1( c1) (Rieske iron sulfur protein, ISP [2Fe2S]) c ( 5A, ) 1997 Xia [43] 2.9Å III 1998 Zhang [44] III 3.0Å ISP c1 ISP Iwata III 11 2.8Å 5 III A: III III b( b562/b H b566/b L ) c 1 ( c 1 ) B: III(PDB code 1BE3) 11 C: (PDB code 1BE3) ( Å) ISP [2Fe2S] b L c 1 ( 5B) Zhang ISP b c1 9 ( FeS presequence) 11 9 2 III 1 2 MPP (mitochondrial processing peptidase ) [45,46] 2000 Hunte [47] III 2.3Å Q6 III III [48] ( 5C) III Qo
573 b L Qi Q site: QH QH + H + e + O 2 P e [2Fe2S](ISP) (movement of ISP) cyt. c1 cyt. c QH Q + H + e + P e cyt. b (b L) cyt. b (b H) Qi site Q site : Q(QH ) + e + H QH (QH ) + i N 2 Qo c Qi c III Q III Xia 2002 2003 III Q Qo Qi [49,50] 8 b [51] Hunte III Qo 5nheptyl6hydroxy 4,7 dioxobenzothiazole Qo [52] Berry III A [53] 2002 Langet Hunte III c III c 2.97Å [54] c III c c1 c III 4 IV(Complex IV) c ( IV EC1.9.3.1) c I II III c 1 1 1 IV 13 210k (heme a1 heme a3) (CuB) (CuA) heme a1 heme a3 CuB SU1 heme a3 CuB FeCu (a3cub) [2Fe2S] CuA SU2 SU3 SU1 SU2 SU1 SU2 SU3 IV c ( 6 IV A: IV (heme a1 heme a3) (CuB) (CuA) C B: IV C: ( Å)
574 6A, ) IV / c c c 1995 Iwata [55] (Paracoccus denitrificans) c 2.8Å SU1 SU2 SU3 SU4 CuA heme a1 heme a3 CuB Hartmut Michel SU1 SU2 2.7Å 1 Mg 2+ ( Mn 2+ ) 1 Ca 2+ [56] 2002 Iwata c ( I 286 ) 2.3Å/2.8Å( ) c 286 / 1995 Tsukihara IV CuA heme a1(fe) heme a3(fe) CuB CuA Mg CuB Zn [57] IV 13 ( 6B) IV 28 12 ( ) SU1 heme a heme a3 CuB SU2 2 heme a3 CuB SU1 SU2 CuA SU3 7 SU1 3 IV SU1 SU2 SU3 [58] IV SU1 SU2 SU3 DNA c c IV ( 6C) IMS side: cyt.c (red.) cyt. c (ox.) + e 3 e CuCu (Cu ) heme a heme a site 3 heme a site: e [FeCu] center Fe OOCu A [FeCu] O (coupled proton translocation) 2 [FeCu] O + H [FeCu] O H coupled proton translocation: H + 2 N 2 H + + N P [FeCu] 4 [FeCu] 1 [FeCu] 1 1 [FeCu] Fe/Cu [59,60] IV [FeCu] c IV D (Dchannel) K (Kchannel) [55,61] H (Hchannel) [59] Iwata [55] c [FeCu] 325 1998 Yoshikawa [59] C 2.3 2.35 2.9 2.8Å
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