Biochimica et Biophysica Acta, 1113 (!¢r~2) 339-373

339

© 1092 Elsevier Science Publishers B.V. A l l rights reserved 0304-4157/q2/$05.00

BB,, ~ E V 85414

Crystal structures of membrane lipids Irmin Pascher, Max Lundmark, Per-Georg Nyholm a:td Staffzm Sufide" Structural Chemistry, Department of Medical Biochemistry and MEDNET Lohoralorv (~Jle~)rg Urlil'~/'~1~..(JO (.~.,"~, ',~('~2en ; (Received 12 May 1992)

Contents I.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

340

II.

Ix :~mcnclaturc. notations, parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .A ' A t o m numbering and configurational notation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 'J. Conformational notation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Chain packing modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

342 342 342 34: M3

I l L Packing arrangements in lipid crystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~. G c n c r d packing principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. Doui"e-chain lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Singlc-chain (l~o)-lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.I. Intcrdigitation of hydrocarlx~n chains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . {'. Interdigitation of h©adgroul~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

~5 -'~5 M5 .145

IV. l.cadgroup packing, lateral interaclions and molecular area . . . . . . . . . . . . . . . . . . . . . . . . . A. Phosphatidic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Phosphatidylglyccrol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Phospha ,idvlct hanolamincs/phosphatidylcholincs . . . . . . . . . . . . . . . . -.............. I. Layct parallel hcad~ro,.tp dipoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. ]nterdigitating hcad~roup dipoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Layer parallel, interdigitating hcadgroep dipoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Glycosphin$olipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.!47

V.

358 ~58 3,,,~ ~,~'JO .~2 .~2 .'~5

346

347 M? 3~2 353 35f 35~ 356

Mol©cular co~fonnation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Diglyceridc/ceramide conformation: C(2)-C(3) rotamcrs and chain stackinlz . . . . . . . . . . . . . B. HeadgrouT~ rotamcrs about t l ~ C ' , )-C~2) gh, ccrol bon:l . . . . . . . . . . . . . . . . . . . . . . C. [referrer' combinations o f CI2}-C'(3) and C( ] } - ( ] 2 ) n~amcrs . . . . . . . . . . . . . . . . . . . . 1. s¢/~ c o , lo;.,ners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. - s c / ~ , conlbrmers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. E l l ] and - s ¢ / i ~ conformc~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. a p / c o n l o r m c r s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Hcadg-:~vps: intern',d conformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I . : [ , : ~ g r o ~ a l . ~ o ¢ pho~phoclhanol~minc ~'pc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. K;irror i m q c ffansition~., o f P E i PC: hcadgroup~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Pho~phoglyccrol headgroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Saccharidc hcadgroup .

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VI. (.onctus~ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................................

Acknowlcdgemcnts

References

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to: I. Pa~clm=r. $sructoral Cllcmistn/, U m ~

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S~-¢1¢n.

371

340

lions arising from the regular hydrocarl~)n chain matrix, which complicate or ~)metimes obstruct Ihc strutlure solution. Although lhe first lipid crystal structure was determined by Mi~ller in the early 1920's 18] it took another 50 years before the first complex mcnbrane lipid, dilauroylphosphatidyicthanolamine, was ~dved 1974 by Shipley and c,)workcr.~ [9]. During ;he recent years, however, cry,~lal structures of more than 30 complex membrane lipids and their ly~)-compounds have been s(flved. These analyses comprise a :ariety of glyccrolipids such ;is acyl- and alkylglyccrols, phosphalidic acids, phosphatidyicthanolamincs, N-nlono- and dimclhylaled phosphalidylethanolamines, phosphalidylcholines, phosphatidylglycerol, as well as sphingolipids and sphingolipid componcnl5 such as sphingosine. ccramides, psychosinc and cerchrosidcs. Lys~)-compounds of membrane iipids, although they ,v,:cur in rather minute amounts in biomembranes -

!. Introduction

X-ray single crystal analyses of c(~mplcx lipids have fundamcnlally contributed to ,mr prcscn! knowledge of the structure and molecular propcrlics ol lipids [1-7]. Crystal structure analysis is '# superior method with regard to dclails in structural infi~rmation - it givc~ not only dclailed confi)rmational featurc*=~ but al.~) prorides insight into intra- and intcrmolccular interactions and packing princip:cs at an accurate ,~tomic level. A drawback of the method when applied to complcx amphipathic lipids are the difficulties encountered with preparation oi pure, homol.guc-frcc species and their successful crystalli;~.'llion. Despite (if the filet that most lipids with saturated hydrocarl~m chai,s spontaneously form crystalline p h a ~ s , the preparation ol high quality single-crystals is often a ra!hcr arduous and unpredictable task, Furtherm,,re, ::-,. Jiffraction patterns of lipid,,, a~c ~sually dominated by strong subcell reflcc-

@

a)

a-chain

"-~

.

~

~'-chain

'

~-chain

b)

:~_ ~. ~'~i~ ~B '~

c)

i~

L. ":~'"~' i ~--•..

" syn-clinal.60%30 ~

. $yn-clin~o ~i,l.60%

•....

- ~,r~t;-clinal

÷anti-clinal

o° ~3o

syn-pertplanar

:~

-,

c-~-,:

t, t a g g e r e d

eclipsed

F~. l, Ntm~nclalur¢ in t:lmt,~malKma! ',dudics of mt'mhranc hl,id,.< (a) Ahmt nt~mhcrmg and notah¢m ol hlr~l,in angh:~, :~,¢c,lrdmg Io .~lin~raiinl~am 14.4.~]. (h) I]k.*tindNm of ~o~.m angle., (el Nol,,i~m ol ~lag~er~'d and ¢chp,,,,ed ;ol~.m :mgk*.. range,, .mcc,i~rdiag h) Kl~,nc an(I

Prch~I.';.~l.

341 e.g., as melatx)lic intermediates and regulators -+ have hecn included in this review+ Their confl~rmatitm and packing arc of great interest a~ thc lateral packing arrangements and interactions of their hcadgroup~ is

less affected by the chain packing and thus +,h(+w Ihc lrue packing requirements, of Ihc hcadgrtmps.

TABLE

Included in this review arc also some crystal structurc~ of iaodificd membrane lipide, or unnatural men~brant: lipid analogucs. ~'hich proxidc valuaMc infi~rma-

lion on i;pid conformation and packing. F,,r r,'ccnt revicv,'s co~cring crystal ~,tttl¢lures t)l lipid~ including long chain fatty acid~, alcohoi~ and

I

('rt'~h,t/ strli('ltiri's o f mt'litdinl~ Ill lhl2 nllmcll(I;illll~: o n l i n a l publicalion+ arc liven. _++ Ahhrc,,iali= m,,

ll~:d ill t'onli>rmdliiln.lf Mudl+'~ + (~'t" Jl~~iycero- I -ph,r~pho+i,i -~lyccrol l)# PF 2.3-dilaur*~l-m -glTccrO,- I -pl~l,,pl~.'lhamflamlnc act:t ic acid D~' .PI:-M t ~,3-dilaur~l-~. -glvccro- I -pho~pho-N-m~lm+mcl h:, Iclhamdaminc DLPt~M, ~.3-dilaut(~,'l-I), -gl~,'cc to- I -pht,*,ph,.I..~/.N-d,mclhylclhanoh,mmc I)MP(" 2.3-dimyri~hi_~l-= ~-glyccm- I -plm~phoch, dinc dlh~;~,rat¢ I)B~ t ' ( ; pT.~ 2.3-di-( I I +hromoundccan~,l )-ll ~l~ccm- ! -p.lolucnesulph~ ,~hdC 5phmgdipul,, (&,uhlc.cham) "4+PSp +%+-h. I r :'c'(~',a m ~ I - phyl< P,p hi ng~,in¢ h:lX-p~p Vii ~,.~n-dihydrox3,~cladcca n(~! )-ph~,hr~ph mgo,,mc ( +I: R I -/3 -, ~-ga lacl*v, yl+ N 4 "- I )* I*l)'d f( )lilyi v.lad¢ca m ,yl b I )- d i hyd rl ~'I ,h ,n~*P.I nc I / 2 c l h a m d ~d~alc

Lipid anah~ ; ~. ;J;,u.~E.+,'haml !)1)-(':*,,~=; I5.15-hi~d,~icok)*+ymclhyllllh~'r¢~n-5 ~ K l i u m Ih;*~..3analc I X ) D M A llr dh~lad¢~.Tldimclh~.lammomum hr~E

.t4Xl

• "s'/ I.I

{t

{

t.l~l!

l-il ~

ll~

pitt, llli~l~

lllll

~.::~.::x~t:x:£~

(~ v v v

duccd in the figures. The pact, rag cross-sc:lil,ns (5" ~ molecular areas) of the lipids in the plane ,ff Ihc hil:lyer arc indicated in the fi~,nrc~, and arc alsl, compiled in Tahle II. II-.4. I'ho,v~handW acM Fig. 8 shows llic packing pallcrns ill Ihc pli~t~,phalc group ill" rlhosph~ilidic acld~ I I ) M P A iind i ) I . P A i lind lys.l-flirln5 (d+itxyitliA ',nil I+I'A: I wh;ch dHf,'r wilh rcH]¢+l hi their stale ti~ ioniialioil ;i~+i ~i)'l :>

\

;

CO

.,""v

/ p t1~" IIC 14ff~

P

tl, • 4C

p f .e~" ~

I , • IIIID ~"alO"~

Ii : 0 (~'11 - ¢ 1 2 1 " C ( 3 ) - 043";I

Fig 14. R(~Larncr~al~m the ~l~crol C~2)-C13) bond: the fqlur¢ ~.h~m~,~Ihc lhrcc ~ilag~rcd. encrgcticalb favoured eon~m'matioes (04 =~c. -sc and ap) ~d Ih¢ g.lycerol o~,l~m, O(21) and O(31) to w,hich lhc h~dr~cart-,~ chains arc altach~d O~ly tl~ O4 = ~c/ amJ ~c/ t(~amc~ alk~ a ~xarail¢l~ackar,.gof i1~ chains.

360 oriented in direction of the layer normal, ~imiiar to lhc glycerol chain in glyccroph(~pholipid wilh sc/y conformation (cf. Fig. 20). l'he observed 45" bends in the ,/- and /3-chains of the cerebrosides may primarily be due co the requirement to create a chain tilt in order to accommodate the chain matrix to the rather large packing cross-section of the sugar headgroup, in tilting structures of glycerolipids usually the entire diglyceride moiety becomes tilted or minor chain bends are formed close to the point of the chain attachment (el. DLG and DMPA , Fig. 7). The formation of a chain t~nd is energetically favoured in proximity to sp: hybridized carbons (CO, C ~ C) [48,65]. It ~ of interest to note that the presence of a double bo~,ds in the 4-5 lx~,i,i~m of the sphingosinc chain and in. eg., vinyl ether derivatives of glycerolipids may be to facilitate the parallel stacking of the chains [66]. The absence of these facilitating features in ~turaled a!kylglycerolipicLs might explain the fact that attempts to obtain well-ordered crystals of double-chain ether lipids have ~) far been unsuccessful. it should be noted, however, that in the structure of CER (Fig. 17), which lacks the 4.5-trans double bond. and in dioctadecyl-dimethylammonium bromide (DODMA Br, Fig. 5) 45° and 911° bends, respectively. are observed in .saturated chains at positions corresponding to d',ose favoured for bend formations in unsaturated or carboxylester chains.

V-H t/,'adgroup rotam,'r, about the glycerol ( ( I ) - C ( D bond NMR studies indicate that in aqueous di%nersions the hcadgroup or membrane lipids can rotate rather indef.,cndently o: ~he diglyceride part [67-691. Thereby the C( I )-CI2) glyc~. ,)1 bond ~rves as ~ fie~hl¢ link. In crystal structures this :,~tational freedom manifests itself by the occurrence ~r all staggered rotamers of O, = / s c , / - s c and / a p about the C11)--C(2) bond (.see, e.g., Fig. 1 5 . . ~ / y ~ n f o r n : e ~ L Fig. Ig sht~vs the threc staggered rotamers /so, / - ,~ and / a p of torsion angle 0: that describes the mutual orientation of the glycerol oxygen 0(11) and O(21) (or the corresixmding atom~ 0 ( ! 1 ) and N(21) in sphingosine) about the C(! )-('(2) glycerol or sphingos,le Ix~l~d.

1/-(~ Preferred combinations o f C(2)-C(31 and C ( i ) ( ¢ ~) rotal, rtt,~ ~,

A matter of great interest is whether there are certain conf'.)rmers of O. or certain combinations ,_& 04/0 ., conformers tha~ are particularly favoured resulting in preferences in the orientation of the headgroup with respect to the dit:lyceride/ceramide pz.rt and thus to the membrane surface. It, Fig. 19 the possible combinations of O, head-

Fig. 15. Preferred conformcr~ of the digly~ride pall ol~.crvcd in cr~tal *,tructur¢ ~, of d~ublc-chum gly~rolipHJ,*,. The ~our cxmformc~ arc i ~ d on the R, : s c / a n d - s c / c o f l ~ l ~ a l k m of Ih< g l ~ l l ; | o~gcns 0(21 ) and 0(31 ) and ~m diffCr~ a! xlwcking n ~ , ~ of I1~ two hydrocarixm chains al~J i~ (for delaiJs ~mlpar¢ ~¢lion V-A a ~ l Fig. |6). Th~ Ihfce glycerol oxygens are marked in black.

y

: (;:

--"

Fig. lb. Fore preferred :t~afo, m c ~ of the digly~crid¢ parl t~4~rv~d in crystal structures of membrane lip/as. The fcmr otmf~wtm, s. whk'h differ with n."sl~'ct to tbe ot~tormalmn of the glyccnd ('(2)-('(3) bond. the chain ~tackin8 and Ibe orientat/xm of tbe glycerol hackbone. can be transfered into each o111¢1"by rolatam or axial d~'q')"lacemenl of Iltc hydrocarbon chain as indicalcd by II1¢ larg~ c~¢n arr, m,.~_ The large ( ~ n a r r * ~ and the small circular arrOv, s indK:alc the changt..'s in chain p~ili(ms and torsi(m angles required to Iran.'~f~rm one c~mi't, mer mlo am*ther tolh~ving the black h,n'i~mtal and vcr;ical arrOWs. The c=~ndinates of I!1¢ tour .~mh)rmers of II1~ di:v.'y|. glycerol m*~icty arc tla~c of DMP(" A. DMP(; B. I)I.FA and I)MIX; A

sc]p

sc/7

C_

group rotamcrs with the different 0~ rotar~cr and chain stacking modes ~f It,,: d~g|yccridc par1 arc ,,hou,'n. For each ~/0: C(mlbination Ihc numl'~: of ,"orreSl~)ndirtg ~tructurc,+ (~'~'~,ed in c~'~t:+l structt,r~, b. given. The structures concern+.d, which a~mpri,~: t~ th single- and double-chain lipids and a Icu, chainlm,~ lipid c(mil~)nenl,, arc shown in Fig:,. 2t1-23. • As indicaled by the .,,chemc in Fig. |9. only lipids with 0~ = ~ / or - s c / conformation g+vc structures with parallclly stacEcd chain.,,. In &~ublc-ehain lipids with 04 = a p / (l:ig. 23) the chains do not stack paralleil. The ill,=stralkms in Fig. 19 a l ~ slueJv that certain combinations of Rag, arc .~h:r=eallyuntav(mrcd, as the headgroup would rotate back into the bilaycr. The.~ unfavourod c.,J~=tormations are the three cxmformcr,, ~ / / ~ / - sc. - . ~ / y / ~ , a=~l - ~ / / J / ~ . The two latter conformers arc. in addition t,) the stcric:l restriction imposed by the membranc layer, unfav,mrcd due to the 1.3-synaxial orientation o+" th+: C ( I ) - O ( I I ) and ('(3)O(31 )bonds. In sphingolipids this effect aim ari~s for the s c / y / a p conformer, as in this mnformation Ihc C(3)-O(31) dipole of the free sphingosine 3-hydro~lgroup becomes co-parallel with the O I )-(X I I) b(md [24,105]. From the numl~:r of (d~ervations (given in parantheses below each of the conformers in Fig. 19) it appears that the + s o / ± sc combinations of 0 ~ / 0 , rotamers arc dominating among the investigated ,~,ructares, despite of the fact that ~ of the + s c / + conforna:rs, mentioned al~we, are excluded in bilaycrs on sterical reasons. From Figs. 2(I and 22 it hec~anes clear that the O~= ~ / a n d - . ~ / c , mformatk)ns about the O2)-C13) glycerol h

Crystal structures of membrane lipids.

Biochimica et Biophysica Acta, 1113 (!¢r~2) 339-373 339 © 1092 Elsevier Science Publishers B.V. A l l rights reserved 0304-4157/q2/$05.00 BB,, ~ E...
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