Science - USA (2020-01-03)

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it seems that resistance to ART carries a bio-

logical trade-off for the parasite: It grows at

a slower rate owing to the decreased avail-

ability of amino acids for protein translation.

Therefore, the unfolded protein response,

which alleviates cellular stress caused by

accumulation of unfolded and misfolded

proteins, is up-regulated in parasites in an

attempt to withstand the toxic effects of re-

active ART metabolites ( 10 , 11 ).

How does PfKelch13 function in he-

moglobin endocytosis? A likely scenario

is that the cysteine-containing Kelch do-

mains, which allow protein-protein inter-

actions, function as a molecular scaffold

to engage PfKelch13 partner proteins to

facilitate hemoglobin transport. Inhibitors

against eukaryotic Kelch proteins disrupt

protein-protein interactions by chemi-

cally modifying the Kelch cysteine residues

( 12 ). This could be an avenue to disrupt

PfKelch13-mediated hemoglobin digestion

and nutrient uptake by the parasite. A rela-

tively unexplored facet of PfKelch13 is the

BTB/POZ domain ( 6 ). In other eukaryotes,

this domain forms a Cullin-3–E3 ubiquitin

ligase complex and promotes the protea-

somal degradation of multiple protein sub-

strates ( 13 ). However, P. falciparum does

not appear to encode a canonical homolog

of Cullin-3, and because PfKelch13 itself

is localized within a distinct subcompart-

ment in the parasite cytoplasm ( 14 ), it will

be interesting to identify how PfKelch13

ubiquitinates proteins.

Pfkelch13 mutation is not the only mech-

anism of ART resistance, because parasites

that display an increased ring-stage sur-

vival phenotype but lack Pfkelch13 muta-

tions have been reported ( 15 ). It would be

intriguing to investigate whether these

parasites also show defects in hemoglobin

uptake. In addition to ART, ACTs include a

partner drug that typically targets the he-

moglobin digestion mechanism of the par-

asite. Future formulations of ACTs might

be more effective by using partner drugs

targeting other biochemical pathways. j

REFERENCES AND NOTES

1. Y. Tu, Nat. Med. 17 , 1217 (2011).


2. “World malaria report 2018” (World Health
   Organization, 2018); http://www.who.int/malaria/
   publications/world-malaria-report-2018/en/.


3. A. M. Dondorp et al., N. Engl. J. Med. 361 , 455 (2009).


4. J. Birnbaum et al., Science 367 , 51 (2020).


5. C. L. Hartwig et al., Biochem. Pharmacol. 77 , 322 (2009).


6. F. Ariey et al., Nature 505 , 50 (2014).


7. J. Straimer et al., Science 347 , 428 (2015).


8. M. Ghorbal et al., Nat. Biotechnol. 32 , 819 (2014).


9. C. Dogovski et al., PLOS Biol. 13 , e1002132 (2015).


10. S. Mok et al., Science 347 , 431 (2015).
    1 1. P. J. Shaw et al., BMC Genomics 16 , 830 (2015).


11. A. Cuadrado et al., Nat. Rev. Drug Discov. 18 , 295 (2019).


12. L. Pintard, A. Willems, M. Peter, EMBO J. 23 , 1681 (2004).


13. J. Birnbaum et al., Nat. Methods 14 , 450 (2017).


14. A. Mukherjee et al., Malar. J. 16 , 195 (2017).
    10.1126/science.aba0445

PHYSICS

Majorana fermions go for a ride

Evidence for propagating Majorana quasiparticles

is found in a topological superconductor

By Sumanta Tewari^1 and Tudor D. Stanescu^2

E

nrico Fermi described Ettore Ma-

jorana as having the mind of a ge-

nius. The Majorana fermion, born

as a testimony to the truthfulness of

mathematical aesthetics, has recently

returned to the center stage of mod-

ern physics. These are particles that are

also their own antiparticles. For decades,

Majorana’s theory was considered a math-

ematical curiosity that has little to do with

reality. However, they have now become

the key concept associated with certain

types of quasiparticles in condensed-mat-

ter systems ( 1 ). In the condensed-matter

context, they are not fundamental particles

like electrons or neutrinos but emerging

excitations that we term quasiparticles. On

page 104 of this issue, Wang et al. ( 2 ) pro-

vide strong evidence for the observation of

Majorana quasiparticles in an iron-based

superconductor, FeSexTe1–x.

The concept of Majorana fermions has its

roots in a celebrated equation discovered in

the late 1920s by physicist Paul Dirac. The

Dirac equation seamlessly brings together

quantum mechanics and the special theory

of relativity and provides the quantum me-

chanical description of spin-half fermions,

such as electrons, protons, and neutrons.

The equation has the property that if a solu-

tion exists with an energy +E, –E is also a

solution. The positive-energy solutions de-

scribe the “regular” particles (for example,

electrons and neutrons), whereas the nega-

tive-energy solutions—initially regarded by

even Dirac as unphysical—are now known

to describe their so-called “antiparticles”

(for example, positrons for electrons and

antineutrons for neutrons). For every quan-

tum mechanical particle that obeys the

Dirac equation, there are subatomic anti-

particles with physical properties that are

identical in some respects to those of the

corresponding particle (for example, the

same mass) and exactly opposite in some

others (for example, baryon numbers and

opposite electric charges). Thus, the nega-

tively charged electron has an antielec-

tron called a positron that is the positively

charged counterpart with equal mass. The

neutron and the antineutron have the same

mass but opposite baryon numbers.

In the late 1930s, Ettore Majorana showed

that the Dirac equation accepts a class of so-

lutions that describes particles that are iden-

tical in every respect to their antiparticles.

The original candidates for Majorana fermi-

ons—neutrons and neutrinos—appeared to

have distinct antiparticles. For neutrinos,

the jury is still out, but the concept of Ma-

jorana fermions has become central to de-

velopments in supersymmetry, dark matter,

and, most recently, certain types of emerg-

ing quasiparticles in condensed-matter sys-

tems. In condensed-matter systems, they

can emerge in a special class of supercon-

Setting the stage

The iron-based

topological superconduc-

tor has a domain wall

(black line) separating

two regions shifted by

one-half of a unit cell.

Bulk

Surface Domain wall

Defning the directions

The reciprocal lattice

points of the bulk

(X, G, Z) and surface

states (X, G) are shown.

X

G

Z

G

X

Topological surface

states

In the bulk, valence and

conducting bands (red) do

not touch. Surface valence

and conduction bands

(blue) touch at one point.

X G X

Majorana QPs

Along the domain wall, a

linear set of allowed low-

energy states (orange)

would connect the gapped

bands of the topological

superconductor.

X G X

Inferring Majorana modes

Indirect observations support the existence of propagating Majorana quasiparticles (QPs) in the presence

of surface topological superconducting states (blue) emerging from the bulk states (red).

3 JANUARY 2020 • VOL 367 ISSUE 6473 23

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