Recoverin

Recoverin structure consists of four EF-hand motifs arranged in a compact array, which contrasts with the dumbbell shape of other calcium-binding proteins like calmodulin and troponin C.{{cite journal | vauthors = Flaherty KM, Zozulya S, Stryer L, McKay DB | title = Three-dimensional structure of recoverin, a calcium sensor in vision | journal = Cell | volume = 75 | issue = 4 | pages = 709–16 | date = November 1993 | pmid = 8242744 | doi = 10.1016/0092-8674(93)90491-8 | doi-access = free }}

Recoverin undergoes a conformational change in a [Ca²⁺]-dependent way. This protein is myristoylated at its amino-terminal.{{cite journal | vauthors = Ray S, Zozulya S, Niemi GA, Flaherty KM, Brolley D, Dizhoor AM, McKay DB, Hurley J, Stryer L | title = Cloning, expression, and crystallization of recoverin, a calcium sensor in vision | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 13 | pages = 5705–5709 | date = July 1992 | pmid = 1385864 | pmc = 49365 | doi = 10.1073/pnas.89.13.5705 | doi-access = free | bibcode = 1992PNAS...89.5705R }} The myristoyl group is sequestered in a hydrophobic cavity of the protein in its Ca²⁺-unbound form. Upon binding of recoverin to Ca²⁺, the group is extruded and inserted into rod membranes,{{cite journal | vauthors = Ames JB, Ishima R, Tanaka T, Gordon JI, Stryer L, Ikura M | title = Molecular mechanics of calcium-myristoyl switches | journal = Nature | volume = 389 | issue = 6647 | pages = 198–202 | date = September 1997 | pmid = 9296500 | doi = 10.1038/38310 | bibcode = 1997Natur.389..198A }} probably facilitating the interaction with membrane-bound GRK1. Specific amino acid residues become exposed to the surface of the recoverin molecule or relocate, possibly forming a site to inhibit GRK1 {{cite journal | vauthors = Valentine KG, Mesleh MF, Opella SJ, Ikura M, Ames JB | title = Structure, topology, and dynamics of myristoylated recoverin bound to phospholipid bilayers | journal = Biochemistry | volume = 42 | issue = 21 | pages = 6333–6340 | date = June 2003 | pmid = 12767213 | doi = 10.1021/bi0206816 }}{{cite journal | vauthors = Tachibanaki S, Nanda K, Sasaki K, Ozaki K, Kawamura S | title = Amino acid residues of S-modulin responsible for interaction with rhodopsin kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 5 | pages = 3313–3319 | date = February 2000 | pmid = 10652319 | doi = 10.1074/jbc.275.5.3313 | doi-access = free }} Solution structures of myristoylated recoverin with and without bound Ca²⁺ have been reported.{{cite journal | vauthors = Tanaka T, Ames JB, Harvey TS, Stryer L, Ikura M | title = Sequestration of the membrane-targeting myristoyl group of recoverin in the calcium-free state | journal = Nature | volume = 376 | issue = 6539 | pages = 444–447 | date = August 1995 | pmid = 7630423 | doi = 10.1038/376444a0 | bibcode = 1995Natur.376..444T }}

The vertebrate retina contains two types of photoreceptors: rods and cones. Rods have been studied more intensively than cones due to their simpler preparation. A rod responds to light by generating a hyperpolarizing electrical response (light response) via the phototransduction cascade located in the rod's outer segment (OS). Rods adapt to varying light conditions by decreasing their sensitivity to prevent saturation, thus enhancing their functionality across a range of ambient light intensities. This process, termed light adaptation, involves modifications to the phototransduction cascade that occur under reduced [Ca2+] levels in the rod OS during light exposure.{{cite journal | vauthors = Nakatani K, Yau KW | title = Calcium and light adaptation in retinal rods and cones | journal = Nature | volume = 334 | issue = 6177 | pages = 69–71 | date = July 1988 | pmid = 3386743 | doi = 10.1038/334069a0 | bibcode = 1988Natur.334...69N }}

The first step in this cascade is the absorption of light by visual pigments. An activated rhodopsin (Rh*) stimulates approximately 100 transducin molecules per second, initiating the cascade. After activating phototransduction, Rh* must be inactivated. Although Rh* naturally decays over time, rhodopsin kinase (GRK1) quenches it more rapidly through phosphorylation. Recoverin plays a role in this process by inhibiting the phosphorylation of Rh* at high [Ca2+] levels{{cite journal | vauthors = Kawamura S, Hisatomi O, Kayada S, Tokunaga F, Kuo CH | title = Recoverin has S-modulin activity in frog rods | journal = The Journal of Biological Chemistry | volume = 268 | issue = 20 | pages = 14579–14582 | date = July 1993 | pmid = 8392055 | doi = 10.1016/s0021-9258(18)82369-9 | doi-access = free }} (see also {{cite journal | vauthors = Hurley JB, Dizhoor AM, Ray S, Stryer L | title = Recoverin's role: conclusion withdrawn | journal = Science | volume = 260 | issue = 5109 | pages = 740 | date = May 1993 | pmid = 8097896 | doi = 10.1126/science.8097896 | bibcode = 1993Sci...260..740H }} by binding to GRK1 rather than Rh*,{{cite journal | vauthors = Chen CK, Inglese J, Lefkowitz RJ, Hurley JB | title = Ca(2+)-dependent interaction of recoverin with rhodopsin kinase | journal = The Journal of Biological Chemistry | volume = 270 | issue = 30 | pages = 18060–18066 | date = July 1995 | pmid = 7629115 | doi = 10.1074/jbc.270.30.18060 | doi-access = free }} thereby extending the lifetime of Rh*.

Understanding the role of recoverin in light adaptation requires noting that [Ca2+] is high in darkness and low under light conditions in the OS.{{cite journal | vauthors = Yau KW, Nakatani K | title = Light-induced reduction of cytoplasmic free calcium in retinal rod outer segment | journal = Nature | volume = 313 | issue = 6003 | pages = 579–582 | date = 1985 | pmid = 2578628 | doi = 10.1038/313579a0 | bibcode = 1985Natur.313..579Y }} Consequently, a flash of light in the dark triggers a prolonged response since recoverin at high [Ca2+] inhibits GRK1, resulting in a longer lifetime for Rh*.

Physiological studies revealed that injection of recoverin into Gecko rods lengthened the flash response duration,{{cite journal | vauthors = Gray-Keller MP, Polans AS, Palczewski K, Detwiler PB | title = The effect of recoverin-like calcium-binding proteins on the photoresponse of retinal rods | journal = Neuron | volume = 10 | issue = 3 | pages = 523–531 | date = March 1993 | pmid = 8461139 | doi = 10.1016/0896-6273(93)90339-S }} while its deletion in mouse rods reduced it,{{cite journal | vauthors = Makino CL, Dodd RL, Chen J, Burns ME, Roca A, Simon MI, Baylor DA | title = Recoverin regulates light-dependent phosphodiesterase activity in retinal rods | journal = The Journal of General Physiology | volume = 123 | issue = 6 | pages = 729–741 | date = June 2004 | pmid = 15173221 | pmc = 2234569 | doi = 10.1085/jgp.200308994 }} aligning with expectations. However, the study in mice revealed that recoverin deletion affects neither the rising phase of a light response nor the response peak (time and amplitude) and facilitates the response recovery time course to shorten the duration. These results can be explained when the phosphorylation of Rh* occurs around or just after the peak of a response in rods.{{cite journal | vauthors = Kawamura S, Tachibanaki S | title = Molecular bases of rod and cone differences | journal = Progress in Retinal and Eye Research | volume = 90 | pages = 101040 | date = September 2022 | pmid = 34974196 | doi = 10.1016/j.preteyeres.2021.101040 }} (The phosphorylation in cones is likely to take place before the response reaches its peak.)

Since the response amplitude determines photoreceptor light sensitivity, recoverin minimally affects the sensitivity to a single flash in the wild-type mouse. However, under continuous light, the response amplitude, and thus the sensitivity, is lower in mice lacking recoverin compared to wild-type mice. This decrease is probably due to a temporal accumulation of single flash responses of shorter duration with unaltered peak amplitude at lowered [Ca²⁺]. Consequently, recoverin sensitizes rods under steady light in wild-type mice, enabling them to detect weak continuous light that would be difficult to recognize without this protein.

In the dark, approximately 10% of total recoverin in the mouse retina is present in the rod OS, and the rest is distributed throughout the rod cell.{{cite journal | vauthors = Sampath AP, Strissel KJ, Elias R, Arshavsky VY, McGinnis JF, Chen J, Kawamura S, Rieke F, Hurley JB | title = Recoverin improves rod-mediated vision by enhancing signal transmission in the mouse retina | journal = Neuron | volume = 46 | issue = 3 | pages = 413–420 | date = May 2005 | pmid = 15882641 | doi = 10.1016/j.neuron.2005.04.006 }} Under light, those in the OS translocate towards rod synaptic terminals, suggesting recoverin may have roles in addition to controlling Rh* lifetime, such as enhancing signal transmission from rods to rod bipolar cells.{{cite journal | vauthors = Strissel KJ, Lishko PV, Trieu LH, Kennedy MJ, Hurley JB, Arshavsky VY | title = Recoverin undergoes light-dependent intracellular translocation in rod photoreceptors | journal = The Journal of Biological Chemistry | volume = 280 | issue = 32 | pages = 29250–29255 | date = August 2005 | pmid = 15961391 | doi = 10.1074/jbc.M501789200 | doi-access = free }} Recoverin is also an antigen of cancer-associated retinopathy.{{cite journal | vauthors = Polans AS, Buczyłko J, Crabb J, Palczewski K | title = A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy | journal = The Journal of Cell Biology | volume = 112 | issue = 5 | pages = 981–989 | date = March 1991 | pmid = 1999465 | pmc = 2288874 | doi = 10.1083/jcb.112.5.981 }}

Two proteins, recoverin in bovine and its frog ortholog, S-modulin, were reported in 1991 as proteins involved in light-adaptation in rod photoreceptors.{{cite journal | vauthors = Dizhoor AM, Ray S, Kumar S, Niemi G, Spencer M, Brolley D, Walsh KA, Philipov PP, Hurley JB, Stryer L | title = Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase | journal = Science | volume = 251 | issue = 4996 | pages = 915–918 | date = February 1991 | pmid = 1672047 | doi = 10.1126/science.1672047 | bibcode = 1991Sci...251..915D }}{{cite journal | vauthors = Kawamura S, Murakami M | title = Calcium-dependent regulation of cyclic GMP phosphodiesterase by a protein from frog retinal rods | journal = Nature | volume = 349 | issue = 6308 | pages = 420–423 | date = January 1991 | pmid = 1846944 | doi = 10.1038/349420a0 | bibcode = 1991Natur.349..420K }}

{{Reflist}}

• {{MeshName|Recoverin}}

{{Calcium-binding proteins}}

{{Eye proteins}}

Category:EF-hand-containing proteins