Proton paths in the sarcoplasmic reticulum Ca2+-ATPase

Karjalainen, Eeva-Liisa; Hauser, Karin; Barth, Andreas

doi:10.1016/j.bbabio.2007.07.010

Cited by 16 publications

(23 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Starting from the occluded Ca 2ϩ -bound [Ca 2 ]E1P state, the protein is phosphorylated during the transition to the E2P state, and Ca 2ϩ ions are released to the sarcoplasmic reticulum. As suggested by Musgaard et al (42), one proton may bind through the N-path from the cytoplasmic side, whereas two protons bind from the luminal side, potentially through the luminal proton pathway suggested by Karjalainen et al (15). At the same time, the C-path starts forming.…”

Section: Discussionmentioning

confidence: 88%

“…Notably, a structure-based in silico analysis of SERCA (15) has proposed that rapid proton binding from the luminal side depends on chains of water molecules. It was suggested that there are two separate hydrated pathways on the luminal side, one for the exit of Ca 2ϩ and one for the entry of H ϩ .…”

Section: What Is the Functional Role Of The C-path?mentioning

confidence: 99%

“…Therefore, there must be at least one ion access pathway at each side of the membrane, but it has also been suggested that the Ca 2ϩ exit and proton entry pathways on the luminal side of SERCA are separate (15). This article provides a focused review of the ion pathways in SERCA, pointing in particular to the possibility of two cytoplasmic pathways, one for proton exit and another for Ca 2ϩ binding.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ion Pathways in the Sarcoplasmic Reticulum Ca2+-ATPase

Bublitz

Musgaard

Poulsen

et al. 2013

Journal of Biological Chemistry

130

121

View full text Add to dashboard Cite

The sarco/endoplasmic reticulum Ca 2؉ -ATPase (SERCA) is a transmembrane ion transporter belonging to the P II -type ATPase family. It performs the vital task of re-sequestering cytoplasmic Ca 2؉ to the sarco/endoplasmic reticulum store, thereby also terminating Ca 2؉ -induced signaling such as in muscle contraction. This minireview focuses on the transport pathways of Ca 2؉ and H ؉ ions across the lipid bilayer through SERCA. The ion-binding sites of SERCA are accessible from either the cytoplasm or the sarco/endoplasmic reticulum lumen, and the Ca 2؉ entry and exit channels are both formed mainly by rearrangements of four N-terminal transmembrane ␣-helices. Recent improvements in the resolution of the crystal structures of rabbit SERCA1a have revealed a hydrated pathway in the C-terminal transmembrane region leading from the ionbinding sites to the cytosol. A comparison of different SERCA conformations reveals that this C-terminal pathway is exclusive to Ca 2؉ -free E2 states, suggesting that it may play a functional role in proton release from the ion-binding sites. This is in agreement with molecular dynamics simulations and mutational studies and is in striking analogy to a similar pathway recently described for the related sodium pump. We therefore suggest a model for the ion exchange mechanism in P II -ATPases including not one, but two cytoplasmic pathways working in concert.P-type ATPases form a large family of transmembrane transporters that couple the energy from ATP hydrolysis to active transport of key cations across biological membranes. These so-called ion pumps are multidomain enzymes that contain polar and charged residues within their transmembrane (TM) 4 domain that mediate binding of the transported ions. For the most well studied members, the sarco/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) and the Na ϩ /K ϩ -ATPase (NKA), the binding sites have been thoroughly described by structural and mutational studies (1-5), whereas the inherently dynamic interactions along the routes of ion entry and exit remain less clear.P-type ATPases generally function according to an alternating access model (6 -8) (also described as an E1/E2 scheme (9 -11)) in which the ion-binding sites are accessible from either the cytoplasmic or extracytoplasmic side, interspersed by occluded states coupled with phosphorylation or dephosphorylation (12-14). Therefore, there must be at least one ion access pathway at each side of the membrane, but it has also been suggested that the Ca 2ϩ exit and proton entry pathways on the luminal side of SERCA are separate (15). This article provides a focused review of the ion pathways in SERCA, pointing in particular to the possibility of two cytoplasmic pathways, one for proton exit and another for Ca 2ϩ binding. The Luminal/Extracellular Pathway: The "Exit Path"The structure of SERCA in the E2P conformation (trapped as a phosphoenzyme intermediate mimicked by BeF 3 Ϫ ) revealed a luminal Ca 2ϩ exit pathway (Exit path) (Fig. 1a) encompassed by TM segments M1-M6 (16, 17). This structu...

show abstract

Section: Discussionmentioning

confidence: 88%

Section: What Is the Functional Role Of The C-path?mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Ion Pathways in the Sarcoplasmic Reticulum Ca2+-ATPase

Bublitz

Musgaard

Poulsen

et al. 2013

Journal of Biological Chemistry

130

121

View full text Add to dashboard Cite

show abstract

“…7c and 8). Here, we propose several possible reasons why H + ,K + -ATPase undergoes a different conformational transition than SERCA upon addition of AlF or BeF, as follows: (1) A widely opened luminal gate is not necessary for releasing H + to the luminal side, since the transfer of H + could proceed according to the Grotthuss mechanism (Karjalainen et al, 2007). (2) Such a luminal-facing conformation might be short-lived because of the highly acidic conditions in the luminal solution in vivo.…”

Section: Implications Of the Structural And Functional Difference Betmentioning

confidence: 98%

Structural and functional characterization of H+,K+-ATPase with bound fluorinated phosphate analogs

Abe

Tani

Fujiyoshi

2010

Journal of Structural Biology

View full text Add to dashboard Cite

“…The reversible or noncovalent inhibitors such as 1,2,3‐trimethyl‐8‐(pentafluorophenylmethoxy) imidazole [1,2‐α] pyridinium iodide (TMPFPIP), a derivative of the imidazole [1,2‐α]pyridine belonging to SCH28080 series, are K + ‐competitive inhibitors and bind with high affinity to the E2 conformation of the H + K + ‐ATPase, which has a low‐affinity binding site for K + . The modeled E2 conformation proposed a single concerted ligand binding site for TMPFPIP occupying the vestibule created by TM5‐6 loop (L809, P810, L811, and C813), TM6 (I814, I816, and F818), and TM8 (Y925, T929, and F932) (18,54). SCH28080 binds to the region of luminal surface consisting of TM4 (A335), TM5‐6 loop (L809), TM6 (C813), and TM8 (Y922 and I940) (55).…”

Section: Inhibitors and Their Mechanism Of Actionmentioning

confidence: 99%

The Nucleotide, Inhibitor, and Cation Binding Sites of P‐type II ATPases

Chourasia

Sastry

2012

Chem Biol Drug Des

View full text Add to dashboard Cite

P-type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport and expulsion of toxic ions from cells. The harmonized toggling of gates in the extra-and intracellular domains explain the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P-type ATPases requires detailed knowledge of thermodynamical, structural, and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca 2+ -ATPase between E1 and E2 transition states have given a impetus to the theorists to work on the Na + K + -and H + K + -ATPase to address important questions about their function. The current review delineates the importance of cation, nucleotide, and inhibitor binding domains, with a focus on the therapeutic potential and biological relevance of the three P-type II ATPases. This will give an insight into the ion selectivity and their conduction across the transmembrane helices of P-type II ATPases, which may pave the way to a range of fundamental questions about the mechanism and aid in the efforts of structure-and analog-based drug design.

show abstract

Proton paths in the sarcoplasmic reticulum Ca2+-ATPase

Cited by 16 publications

References 69 publications

Ion Pathways in the Sarcoplasmic Reticulum Ca2+-ATPase

Ion Pathways in the Sarcoplasmic Reticulum Ca2+-ATPase

Structural and functional characterization of H+,K+-ATPase with bound fluorinated phosphate analogs

The Nucleotide, Inhibitor, and Cation Binding Sites of P‐type II ATPases

Contact Info

Product

Resources

About