Structure of respiratory complex I - An emerging blueprint for the mechanism

Abstract

Complex I is one of the major respiratory complexes, conserved from bacteria to mammals. It oxidises NADH, reduces quinone and pumps protons across the membrane, thus playing a central role in the oxidative energy metabolism. In this review we discuss our current state of understanding the structure of complex I from various species of mammals, plants, fungi, and bacteria, as well as of several complex I-related proteins. By comparing the structural evidence from these systems in different redox states and data from mutagenesis and molecular simulations, we formulate the mechanisms of electron transfer and proton pumping and explain how they are conformationally and electrostatically coupled. Finally, we discuss the structural basis of the deactivation phenomenon in mammalian complex I.

Figure 1

Structure of mammalian complex I. Structure of the mammalian complex I with 14 core subunits coloured and annotated and the remaining supernumerary subunits shown in grey. Substrates and cofactors are annotated.

Figure 2. Mechanism proposal for complex I.

a. A schematic representation of complex I divided into the major functional domains illustrates the recently proposed mechanism with further details available in Ref. [30]. In the open state, the Q cavity is sufficiently enlarged to allow free passage of quinone in and quinol out of the cavity. The water wire between the PA and MA is broken by the rotation of ND6_TMH3 (in grey). In the closed state, quinone can bind in the deep site and accept electrons, leading to the relocation of chemical protons from the E-channel/ND2 interface via the newly established water wire connection into the tightly enclosed Q cavity. This creates a strong negative charge near ND2 GluTM5/LysTM7 pair, initiating a series of protonation/de-protonation events (indicated by arrows), driven by electrostatic interactions. Eventually this leads to the expulsion of four protons into IMS (P-side) via ND5. The coloured circles represent glutamate or aspartate residues (red), lysine residues (blue) or histidine residues (cyan) in a same relative spatial arrangement as in the mammalian complex I structure. Full circles denote charged residues (negatively in the case of Glu/Asp and positively in the case of Lys) and empty circles denote neutral residues. Charge of histidines is not clear from current structures. b. An alternative mechanistic proposal from Parey et al. [6] (reproduced with permission). Note the presence of a long-lived negatively charged intermediate Q# and different proton paths for the chemical and pumped protons. In short, it is proposed that after transfer of each electron to Q, Q# moves to the second site near a putative proton-loading site (PLS) and accepts a chemical proton (yellow) from the matrix (cycle repeats twice). Each protonation of Q^# leads to injection of pumped proton (green) from the PLS into E-channel (red) and further towards antiporters. For each Q to QH2 reaction, two pumped protons are injected via PLS, driving two more pumped protons via antiporters. See Ref. [6] for details.