Abstract
Proper localization of newly synthesized proteins is essential to cellular function. Among different protein localization modes, the signal recognition particle (SRP) and SRP receptor (SR) constitute the conserved targeting machinery in all three life kingdoms and mediate about one third of the protein targeting reactions. Based on experimental and computational studies, a detailed molecular model is proposed to explain how this molecular machinery governs the efficiency and fidelity of protein localizations. In this targeting machinery, two distinct SRP GTPases are contained into the SRP and SR that are responsible to the interactions between SRP and SR. These two GTPases can interact with one another through a series of sequential and discrete interaction states that are the early intermediate formation, stable complex association, and GTPase activation. In contrast to canonical GTPases, a floppy and open conformation adopted in free SRP GTPases can facilitate efficient GTP/GDP exchange without the aid of any external factors. As the apo-form free SRP GTPases can adopt the conformational states of GDP- or GTP-bound form, the binding of GTP/GDP follows a mechanism of conformational selection. In the first step of complex formation, the two SRP GTPases can rapidly assemble into an unstable early intermediate by selecting and stabilizing one another’s primed states from the equilibrium conformational ensemble. Subsequently, extensive inter- and intra-domain changes rearrange the early complex into a tight and closed state of stable complex through induced fit mechanism. Upon stable complex association, further tune of several important interaction networks activates the SRP GTPase for GTP hydrolysis. These different conformational states are coupled to corresponding protein targeting events, in which the complex formation deliveries the translating ribosome to the target membrane and the GTPase activation couples to the cargo release from SRP-SR machinery to the translocation channel. It is thus suggested that the SRP GTPases constitute a self-sufficient system to execute exquisite spatial and temporal control of the complex targeting process. The working mechanism of the SRP and SR provides a novel paradigm of how the protein machinery functions in controlling diverse biological processes efficiently and faithfully.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- cpSRP:
-
chloroplast SRP
- cpSR:
-
chloroplast SR
- Ffh:
-
SRP54 homologous protein in bacteria and archaea
- FtsY:
-
SRα homologous protein in bacteria and archera
- GDP:
-
guanosine diphosphate
- GTP:
-
guanosine triphosphate
- IBD:
-
insertion box domain
- RNC:
-
ribosome nascent chain complex
- SRP:
-
signal recognition particle
- SR:
-
SRP receptor
- T.aq.:
-
Thermus aquaticus
References
Tokuriki N, Tawfik DS (2009) Protein dynamism and evolvability. Science 324(5924):203–207
James LC, Tawfik DS (2003) Conformational diversity and protein evolution – a 60-year-old hypothesis revisited. Trends Biochem Sci 28(7):361–368
Henzler-Wildman K, Kern D (2007) Dynamic personalities of proteins. Nature 450:964–972
Austin RH, Beeson KW, Eisenstein L, Frauenfelder H, Gunsalus IC (1975) Dynamics of ligand-binding to myoglobin. Biochemistry 14(24):5355–5373
Spence JCH, Weierstall U, Chapman HN (2012) X-ray lasers for structural and dynamic biology. Rep Prog Phys 75(10):102601
Kay LE (2005) NMR studies of protein structure and dynamics. J Magn Reson 173(2):193–207
Ishima R, Torchia DA (2000) Protein dynamics from NMR. Nat Struct Biol 7(9):740–743
Neutze R, Moffat K (2012) Time-resolved structural studies at synchrotrons and X-ray free electron lasers: opportunities and challenges. Curr Opin Struct Biol 22(5):651–659
Aquila A, Hunter MS, Doak RB, Kirian RA, Fromme P, White TA, Andreasson J, Arnlund D, Bajt S, Barends TRM, Barthelmess M, Bogan MJ, Bostedt C, Bottin H, Bozek JD, Caleman C, Coppola N, Davidsson J, DePonte DP, Elser V, Epp SW, Erk B, Fleckenstein H, Foucar L, Frank M, Fromme R, Graafsma H, Grotjohann I, Gumprecht L, Hajdu J, Hampton CY, Hartmann A, Hartmann R, Hauriege S, Hauser G, Hirsemann H, Holl P, Holton JM, Hoemke A, Johansson L, Kimmel N, Kassemeyer S, Krasniqi F, Kuehnel K, Liang M, Lomb L, Malmerberg E, Marchesini S, Martin AV, Maia FRNC, Messerschmidt M, Nass K, Reich C, Neutze R, Rolles D, Rudek B, Rudenko A, Schlichting I, Schmidt C, Schmidt KE, Schulz J, Seibert MM, Shoeman RL, Sierra R, Soltau H, Starodub D, Stellato F, Stern S, Strueder L, Timneanu N, Ullrich J, Wang X, Williams GJ, Weidenspointner G, Weierstall U, Wunderer C, Barty A, Spence JCH, Chapman HN (2012) Time-resolved protein nanocrystallography using an X-ray free-electron laser. Opt Express 20(3):2706–2716
Elmlund H, Baraznenok V, Linder T, Szilagyi Z, Rofougaran R, Hofer A, Hebert H, Lindahl M, Gustafsson CM (2009) Cryo-EM reveals promoter DNA binding and conformational flexibility of the general transcription factor TFIID. Structure 17(11):1442–1452
Heymann JB, Conway JF, Steven AC (2004) Molecular dynamics of protein complexes from four-dimensional cryo-electron microscopy. J Struct Biol 147(3):291–301
Torres T, Levitus M (2007) Measuring conformational dynamics: a new FCS-FRET approach. J Phys Chem B 111(25):7392–7400
Weiss S (2000) Measuring conformational dynamics of biomolecules by single molecule fluorescence spectroscopy. Nat Struct Biol 7(9):724–729
Weiss S (1999) Fluorescence spectroscopy of single biomolecules. Science 283(5408):1676–1683
Barth A (2007) Infrared spectroscopy of proteins. Biochim Biophys Acta Bioenerg 1767(9):1073–1101
Gabel F, Bicout D, Lehnert U, Tehei M, Weik M, Zaccai G (2002) Protein dynamics studied by neutron scattering. Q Rev Biophys 35(4):327–367
Yang WT, Lee TS (1995) A density-matrix divide-and-conquer approach for electronic-structure calculations of large molecules. J Chem Phys 103(13):5674–5678
Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M (1999) Fragment molecular orbital method: an approximate computational method for large molecules. Chem Phys Lett 313(3–4):701–706
Nakano T, Kaminuma T, Sato T, Akiyama Y, Uebayasi M, Kitaura K (2000) Fragment molecular orbital method: application to polypeptides. Chem Phys Lett 318(6):614–618
Zhang DW, Zhang JZH (2003) Molecular fractionation with conjugate caps for full quantum mechanical calculation of protein-molecule interaction energy. J Chem Phys 119(7):3599–3605
Xie W, Gao J (2007) Design of a next generation force field: the X-Pol potential. J Chem Theory Comput 3(6):1890–1900
Hu H, Yang W (2008) Free energies of chemical reactions in solution and in enzymes with Ab initio quantum mechanics/molecular mechanics methods. Annu Rev Phys Chem 59:573–601
Song L, Han J, Lin YL, Xie W, Gao J (2009) Explicit polarization (X-Pol) potential using Ab initio molecular orbital theory and density functional theory. J Phys Chem A 113(43):11656–11664
Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber Ff99sb protein force field. Proteins Struct Funct Bioinform 78(8):1950–1958
MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102(18):3586–3616
Takada S (2012) Coarse-grained molecular simulations of large biomolecules. Curr Opin Struct Biol 22(2):130–137
Zhang Z, Pfaendtner J, Grafmueller A, Voth GA (2009) Defining coarse-grained representations of large biomolecules and biomolecular complexes from elastic network models. Biophys J 97(8):2327–2337
Yang L, Shao Q, Gao Y (2012) Enhanced sampling method in molecular simulations. Prog Chem 24(6):1199–1213
Hu Y, Hong W, Shi Y, Liu H (2012) Temperature-accelerated sampling and amplified collective motion with adiabatic reweighting to obtain canonical distributions and ensemble averages. J Chem Theory Comput 8(10):3777–3792
Kaestner J (2011) Umbrella sampling. Wiley Interdiscip Rev Comput Mol Sci 1(6):932–942
Fiore CE, da Luz MGE (2010) Comparing parallel- and simulated-tempering-enhanced sampling algorithms at phase-transition regimes. Phys Rev E 82(3):031104-1–031104-11
Markwick PRL, McCammon JA (2011) Studying functional dynamics in bio-molecules using accelerated molecular dynamics. Phys Chem Chem Phys 13(45):20053–20065
Haider S, Parkinson GN, Neidle S (2008) Molecular dynamics and principal components analysis of human telomeric quadruplex multimers. Biophys J 95(1):296–311
Chodera JD, Swope WC, Pitera JW, Seok C, Dill KA (2007) Use of the weighted histogram analysis method for the analysis of simulated and parallel tempering simulations. J Chem Theory Comput 3(1):26–41
Chan KY, Trabuco LG, Schreiner E, Schulten K (2012) Cryo-electron microscopy modeling by the molecular dynamics flexible fitting method. Biopolymers 97(9):678–686
Zheng W, Tekpinar M (2011) Accurate flexible fitting of high-resolution protein structures to small-angle X-ray scattering data using a coarse-grained model with implicit hydration shell. Biophys J 101(12):2981–2991
Torbeev VY, Raghuraman H, Hamelberg D, Tonelli M, Westler WM, Perozo E, Kent SBH (2011) Protein conformational dynamics in the mechanism of HIV-1 protease catalysis. Proc Natl Acad Sci USA 108(52):20982–20987
Zhuang W, Sgourakis NG, Li Z, Garcia AE, Mukamel S (2010) Discriminating early stage a beta 42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study. Proc Natl Acad Sci USA 107(36):15687–15692
Zhang B, Miller TF III (2010) Hydrophobically stabilized open state for the lateral gate of the Sec translocon. Proc Natl Acad Sci USA 107(12):5399–5404
Silva JR, Pan H, Wu D, Nekouzadeh A, Decker KF, Cui J, Baker NA, Sept D, Rudy Y (2009) A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. Proc Natl Acad Sci USA 106(27):11102–11106
Nussinov R, Ma B (2012) Protein dynamics and conformational selection in bidirectional signal transduction. BMC Biol 10:2
Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in biomolecular recognition. Nat Chem Biol 5(11):789–796
Saraogi I, Shan SO (2011) Molecular mechanism of co-translational protein targeting by the signal recognition particle. Traffic 12(5):535–542
Pool MR (2005) Signal recognition particles in chloroplasts, bacteria, yeast and mammals (review). Mol Membr Biol 22(1–2):3–15
Park E, Rapoport TA (2012) Mechanisms of Sec61/SecY-mediated protein translocation across membranes. In: Rees DC (ed) Annual review of biophysics, vol 41, Annual Rieviews, Palo Alto California, pp 21–40
Cheng ZL (2010) Protein translocation through the Sec61/SecY channel. Biosci Rep 30(3):201–207
Driessen AJM, Nouwen N (2008) Protein translocation across the bacterial cytoplasmic membrane. Annu Rev Biochem 77:643–667
Traeger C, Rosenblad MA, Ziehe D, Garcia-Petit C, Schrader L, Kock K, Richter CV, Klinkert B, Narberhaus F, Herrmann C, Hofmann E, Aronsson H, Schuenemann D (2012) Evolution from the prokaryotic to the higher plant chloroplast signal recognition particle: the signal recognition particle RNA is conserved in plastids of a wide range of photosynthetic organisms. Plant Cell 24(12):4819–4836
Richter CV, Bals T, Schunemann D (2010) Component interactions, regulation and mechanisms of chloroplast signal recognition particle-dependent protein transport. Eur J Cell Biol 89(12):965–973
Rosenblad MA, Gorodkin J, Knudsen B, Zwieb C, Samuelsson T (2003) SRPDB: signal recognition particle database. Nucleic Acids Res 31(1):363–364
Rapoport TA (2007) Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 450(7170):663–669
Zwieb C, Van Nues RW, Rosenblad MA, Brown JD, Samuelsson T (2005) A nomenclature for all signal recognition particle RNAs. RNA-A Publ RNA Soc 11(1):7–13
Zhang DW, Shan SO (2012) Translation elongation regulates substrate selection by the signal recognition particle. J Biol Chem 287(10):7652–7660
Halic M, Becker T, Pool MR, Spahn CMT, Grassucci RA, Frank J, Beckmann R (2004) Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature 427(6977):808–814
Calo D, Eichler J (2011) Crossing the membrane in archaea, the third domain of life. Biochim Biophys Acta Biomembr 1808(3):885–891
Dalbey RE, Kuhn A (2012) Protein traffic in gram-negative bacteria – how exported and secreted proteins find their way. Fems Microbiol Rev 36(6):1023–1045
Verstraeten N, Fauvart M, Versees W, Michiels J (2011) The universally conserved prokaryotic GTPases. Microbiol Mol Biol Rev 75(3):507–542
von Loeffelholz O, Knoops K, Ariosa A, Zhang X, Karuppasamy M, Huard K, Schoehn G, Berger I, Shan SO, Schaffitzel C (2013) Structural basis of signal sequence surveillance and selection by the SRP–FTSY complex. Nat Struct Mol Biol 5:604–610
Hainzl T, Huang SH, Merilainen G, Brannstrom K, Sauer-Eriksson AE (2011) Structural basis of signal-sequence recognition by the signal recognition particle. Nat Struct Mol Biol 18(3):389–391
Focia PJ, Shepotinovskaya IV, Seidler JA, Freymann DM (2004) Heterodimeric GTPase core of the SRP targeting complex. Science 303(5656):373–377
Egea PF, Shan SO, Napetschnig J, Savage DF, Walter P, Stroud RM (2004) Substrate twinning activates the signal recognition particle and its receptor. Nature 427(6971):215–221
Montoya G, Svensson C, Luirink J, Sinning I (1997) Crystal structure of the NG domain from the signal-recognition particle receptor FtsY. Nature 385(6614):365–368
Freymann DM, Keenan RJ, Stroud RM, Walter P (1997) Structure of the conserved GTPase domain of the signal recognition particle. Nature 385(6614):361–364
Hainzl T, Huang SH, Sauer-Eriksson AE (2007) Interaction of signal-recognition particle 54 GTPase domain and signal-recognition particle RNA in the free signal-recognition particle. Proc Natl Acad Sci USA 104:14911–14916
Rosendal KR, Wild K, Montoya G, Sinning L (2003) Crystal structure of the complete core of archaeal signal recognition particle and implications for interdomain communication. Proc Natl Acad Sci USA 100(25):14701–14706
Batey RT, Rambo RP, Lucast L, Rha B, Doudna JA (2000) Crystal structure of the ribonucleoprotein core of the signal recognition particle. Science 287(5456):1232–1239
Neher SB, Bradshaw N, Floor SN, Gross JD, Walter P (2008) SRP RNA controls a conformational switch regulating the SRP-SRP receptor interaction. Nat Struct Mol Biol 15(9):916–923
Siu FY, Spanggord RJ, Doudna JA (2007) SRP RNA provides the physiologically essential GTPase activation function in cotranslational protein targeting. RNA-A Publ RNA Soc 13(2):240–250
Zhang X, Lam VQ, Mou Y, Kimura T, Chung J, Chandrasekar S, Winkler JR, Mayo SL, Shan SO (2011) Direct visualization reveals dynamics of a transient intermediate during protein assembly. Proc Natl Acad Sci USA 108(16):6450–6455
Shen K, Arslan S, Akopian D, Ha T, Shan SO (2012) Activated GTPase movement on an RNA scaffold drives co-translational protein targeting. Nature 492(7428):271–275
Shan SO, Walter P (2005) Co-translational protein targeting by the signal recognition particle. FEBS Lett 579(4):921–926
Jagath JR, Rodnina MV, Lentzen G, Wintermeyer W (1998) Interaction of guanine nucleotides with the signal recognition particle from Escherichia coli. Biochemistry 37(44):15408–15413
Peluso P, Shan SO, Nock S, Herschlag D, Walter P (2001) Role of SRP RNA in the GTPase cycles of Ffh and FtsY. Biochemistry 40(50):15224–15233
Padmanabhan S, Freymann DM (2001) The conformation of bound GMPPNP suggests a mechanism for gating the active site of the SRP GTPase. Structure 9(9):859–867
Ramirez UD, Minasov G, Focia PJ, Stroud RM, Walter P, Kuhn P, Freymann DM (2002) Structural basis for mobility in the 1.1 Angstrom crystal structure of the NG domain of Thermus aquaticus Ffh. J Mol Biol 320(4):783–799
Gawronski-Salerno J, Coon JSV, Focia PJ, Freymann DM (2007) X-ray structure of the T-aquaticus FtsY: GDP complex suggests functional roles for the C-terminal helix of the SRP GTPases. Proteins Struct Funct Bioinform 66(4):984–995
Reyes CL, Rutenber E, Walter P, Stroud RM (2007) X-ray structures of the signal recognition particle receptor reveal targeting cycle intermediates. PLoS One 2(7):e607
Ramirez UD, Focia PJ, Freymann DM (2008) Nucleotide-binding flexibility in ultrahigh-resolution structures of the SRP GTPase Ffh. Acta Crystallogr Sect D Biol Crystallogr 64:1043–1053
Yang MJ, Zhang X, Han KL (2010) Molecular dynamics simulation of SRP GTPases: towards an understanding of the complex formation from equilibrium fluctuations. Proteins Struct Funct Bioinform 78(10):2222–2237
Yang MJ, Pang XQ, Zhang X, Han KL (2011) Molecular dynamics simulation reveals preorganization of the chloroplast FtsY towards complex formation induced by GTP binding. J Struct Biol 173(1):57–66
Zhang X, Kung S, Shan SO (2008) Demonstration of a multistep mechanism for assembly of the SRP·SRP receptor complex: implications for the catalytic role of SRP RNA. J Mol Biol 381(3):581–593
Boehr DD, Wright PE (2008) How do proteins interact? Science 320(5882):1429–1430
Focia PJ, Gawronski-Salerno J, Coon JSV, Freymann DM (2006) Structure of a GDP:ALF4 complex of the SRP GTPases Ffh and FtsY, and identification of a peripheral nucleotide interaction site. J Mol Biol 360(3):631–643
Gawronski-Salerno J, Freymann DM (2007) Structure of the GMPPNP-stabilized NG domain complex of the SRP GTPases Ffh and FtsY. J Struct Biol 158(1):122–128
Ataide SF, Schmitz N, Shen K, Ke A, Shan SO, Doudna JA, Ban N (2011) The crystal structure of the signal recognition particle in complex with its receptor. Science 331(6019):881–886
Yang MJ, Zhang X (2011) Molecular dynamics simulations reveal structural coordination of Ffh-FtsY heterodimer toward GTPase activation. Proteins Struct Funct Bioinform 79(6):1774–1785
Shan SO, Stroud RM, Walter P (2004) Mechanism of association and reciprocal activation of two GTPases. PLoS Biol 2(10):1572–1581
Gasper R, Meyer S, Gotthardt K, Sirajuddin M, Wittinghofer A (2009) It takes two to tango: regulation of G proteins by dimerization. Nat Rev Mol Cell Biol 10(6):423–429
Celedon JM, Cline K (2013) Intra-plastid protein trafficking: how plant cells adapted prokaryotic mechanisms to the eukaryotic condition. Biochim Biophys Acta Mol Cell Res 1833(2):341–351
Jaru-Ampornpan P, Chandrasekar S, Shan SO (2007) Efficient interaction between two GTPases allows the chloroplast SRP pathway to bypass the requirement for an SRP RNA. Mol Biol Cell 18(7):2636–2645
Nguyen TX, Chandrasekar S, Neher S, Walter P, Shan SO (2011) Concerted complex assembly and GTPase activation in the chloroplast signal recognition particle. Biochemistry 50(33):7208–7217
Stengel KF, Holdermann I, Wild K, Sinning I (2007) The structure of the chloroplast signal recognition particle (SRP) receptor reveals mechanistic details of SRP GTPase activation and a conserved membrane targeting site. FEBS Lett 581(29):5671–5676
Chandrasekar S, Chartron J, Jaru-Ampornpan P, Shan SO (2008) Structure of the chloroplast signal recognition particle (SRP) receptor: domain arrangement modulates SRP-receptor interaction. J Mol Biol 375(2):425–436
Peluso P, Herschlag D, Nock S, Freymann DM, Johnson AE, Walter P (2000) Role of 4.5s RNA in assembly of the bacterial signal recognition particle with its receptor. Science 288(5471):1640–1643
Bradshaw N, Walter P (2007) The signal recognition particle (SRP) RNA links conformational changes in the SRP to protein targeting. Mol Biol Cell 18(7):2728–2734
Estrozi LF, Boehringer D, Shan SO, Ban N, Schaffitzel C (2011) Cryo-EM structure of the E. coli translating ribosome in complex with SRP and its receptor. Nat Struct Mol Biol 18(1):88–90
Zhang X, Rashid R, Wang K, Shan SO (2010) Sequential checkpoints govern substrate selection during cotranslational protein targeting. Science 328(5979):757–760
Zhang X, Schaffitzel C, Ban N, Shan SO (2009) Multiple conformational switches in a GTPase complex control co-translational protein targeting. Proc Natl Acad Sci USA 106(6):1754–1759
de Leeuw E, Kaat KT, Moser C, Menestrina G, Demel R, de Kruijff B, Oudega B, Luirink J, Sinning I (2000) Anionic phospholipids are involved in membrane association of FtsY and stimulate its GTPase activity. EMBO J 19(4):531–541
Lam VQ, Akopian D, Rome M, Henningsen D, Shan SO (2010) Lipid activation of the signal recognition particle receptor provides spatial coordination of protein targeting. J Cell Biol 190(4):623–635
Akopian D, Dalal K, Shen K, Duong F, Shan SO (2013) SecYEG activates GTPases to drive the completion of cotranslational protein targeting. J Cell Biol 200(4):397–405
Shan SO, Schmid SL, Zhang X (2009) Signal recognition particle (SRP) and SRP receptor: a new paradigm for multistate regulatory GTPases. Biochemistry 48(29):6696–6704
Bradshaw N, Neher SB, Booth DS, Walter P (2009) Signal sequences activate the catalytic switch of SRP RNA. Science 323(5910):127–130
Shen K, Zhang X, Shan SO (2011) Synergistic actions between the SRP RNA and translating ribosome allow efficient delivery of the correct cargos during cotranslational protein targeting. RNA-A Publ RNA Soc 17(5):892–902
Schotte F, Cho HS, Kaila VRI, Kamikubo H, Dashdorj N, Henry ER, Graber TJ, Henning R, Wulff M, Hummer G, Kataoka M, Anfinrud PA (2012) Watching a signaling protein function in real time via 100-ps time-resolved Laue crystallography. Proc Natl Acad Sci USA 109(47):19256–19261
Acknowledgement
We thank Dr. Xin Zhang for his insightful comments to this manuscript. This work was supported by the National Basic Research Program of China (2013CB834604).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Yang, M., Pang, X., Han, K. (2014). Multi-state Targeting Machinery Govern the Fidelity and Efficiency of Protein Localization. In: Han, Kl., Zhang, X., Yang, Mj. (eds) Protein Conformational Dynamics. Advances in Experimental Medicine and Biology, vol 805. Springer, Cham. https://doi.org/10.1007/978-3-319-02970-2_16
Download citation
DOI: https://doi.org/10.1007/978-3-319-02970-2_16
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-02969-6
Online ISBN: 978-3-319-02970-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)