Researchers piece together the LanCL puzzle

Date

05/04/21

By Ananya Sen, University of Illinois at Urbana-Champaign


Researchers from the Carl R. Woese Institute for Genomic Biology, including chemistry professor Wilfred van der Donk, collaborated with scientists at Oxford University on a paper recently published in Cell revealing the function of LanCL proteins, which have been found in eukaryotic cells for years but their function was unknown.

The study is the first step towards understanding the importance of these ubiquitous proteins.

Bacteria contain enzymes called LanC that are capable of producing small proteins called lanthipeptides, which are characterized by the addition of a thiol group to a modified serine or threonine amino acid. Similar proteins—called LanC-like or LanCL—have been found in different eukaryotic cells for decades, but their function was unknown.

"LanCLs are found in nearly all higher organisms, including humans. Although scientists have worked on these proteins for over 20 years, we didn't know their function. We had several hypotheses, which we kept ruling out based on our experiments," said Wilfred van der Donk (MMG), Richard E. Heckert Endowed Chair in Chemistry and Howard Hughes Medical Institute Investigator.

A diagram showing Removing the phosphate group from kinases can activate them, which can be problematic. LanCL adds glutathione to these kinases, after which they became deactivated.
Removing the phosphate group from kinases can activate them, which can be problematic. LanCL adds glutathione to these kinases, after which they became deactivated. Credit: Wilfred van der Donk

The first breakthrough came in 2015, when the Nair lab in the Department of Biochemistry solved the crystal structure of a LanC-containing protein in bacteria. The protein was bound to another enzyme called a kinase, which modifies proteins by adding a phosphate group. Inspired by this discovery, the researchers tested whether LanCL proteins were also binding to kinases in eukaryotic cells. "We saw that they were able to bind to many kinases, including AKT and mTOR, and all of a sudden the pieces of the puzzle started forming a picture," van der Donk said.

The next piece fell into place in collaboration with Benjamin Davis, a professor of chemistry at the University of Oxford. The Davis group showed that eliminating a particular phosphate group in kinases causes them to become activated. Scientists had assumed that such processed proteins would be inactive. Together, the Illinois and Oxford groups were able to show that LanCL adds glutathione to kinases with eliminated phosphate groups, after which the kinases became deactivated. "We realized that when the LanCL proteins are absent, the cell has a big problem because there are active proteins floating around that need to be turned off," van der Donk said.

The importance of these proteins became evident in mice that lacked them. "A third of the mice that lack these enzymes die when they are between four to six months old. They die suddenly without getting sick and we still don't understand why," said Jie Chen (GNDP), a professor of cell and developmental biology.

The researchers are interested in understanding the role of these proteins and making a complete list of all the possible targets of LanCLs. "When you have abnormal kinases, it can cause all kinds of problems, including cancer. LanCL proteins eliminate these damaged kinases and it is possible that they also affect other proteins that we are not aware of. We need to connect their cellular functions to the results we saw in the mice," Chen said.

"This study is just the tip of the iceberg. Since these proteins are found everywhere, you can also imagine their effects in feedstock and the future of farming," said Satish Nair (MME/MMG), Head of the Department of Biochemistry.

"This study was possible because of the persistence of our graduate students. Most of us would have given up long ago because the studies were initially going nowhere," Nair said. "It also shows the importance of exploratory research, where you're essentially just looking around. Although it is risky, it is great to see that there are rewards for students who stick it out," van der Donk said.

The paper "LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome" was published in Cell.

More information: Kuan-Yu Lai et al, LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome, Cell (2021). DOI: 10.1016/j.cell.2021.04.001

Read more about this research: Piecing together a puzzle in protein damage - Rosalind Franklin Institute (rfi.ac.uk)

Related People

vddonk

Directory

scheelinAlexander
Scheeline
bjmccallBenjamin
McCall
r-gennisRobert
Gennis
j-gerltJohn
Gerlt
sgranickSteve
Granick
mgruebelMartin
Gruebele
hergenroPaul
Hergenrother
huangRaven
Huang
mlkraftMary
Kraft
leckbandDeborah
Leckband
yi-luYi
Lu
martinisSusan
Martinis
snairSatish
Nair
eoldfielEric
Oldfield
cmsCharles
Schroeder
zanZaida
Luthey-Schulten
selvinPaul
Selvin
sksScott
Silverman
s-sligarStephen
Sligar
tajkhorsEmad
Tajkhorshid
zhao5Huimin
Zhao
pbraunPaul
Braun
mdburkeMartin
Burke
jeffchanJefferson
Chan
sdenmarkScott
Denmark
dlottDana
Dlott
foutAlison
Fout
agewirthAndrew
Gewirth
ggirolamGregory
Girolami
sohirataSo
Hirata
jainPrashant
Jain
jkatzeneJohn
Katzenellenbogen
nmakriNancy
Makri
douglasmDouglas
Mitchell
jsmooreJeffrey
Moore
murphycjCatherine
Murphy
r-nuzzoRalph
Nuzzo
dimerPhilip
Phillips
rauchfuzThomas
Rauchfuss
joaquinrJoaquín
Rodríguez-López
sarlahDavid
Sarlah
kschweizKenneth
Schweizer
jsweedleJonathan
Sweedler
vddonkWilfred
van der Donk
renskeRenske
van der Veen
vuraweisJosh
Vura-Weis
mcwhite7M.
White
sczimmerSteven
Zimmerman
beakPeter
Beak
wklemperWalter
Klemperer
jdmcdonaJ.
McDonald
pogoreloTaras
Pogorelov
mshen233Mei
Shen
dewoonDavid
Woon
wboulangWilliam
Boulanger
rxbRohit
Bhargava
qchen20Qian
Chen
jianjuncJianjun
Cheng
hy66Hong
Yang
andinomaJosé
Andino Martinez
decosteDonald
DeCoste
thhuangTina
Huang
tjhummelThomas
Hummel
dkellDavid
Kell
doctorkMichael
Koerner
marvilleKelly
Marville
crrayChristian
Ray
tlbrownTheodore
Brown
rmcoatesRobert
Coates
thdjrThom
Dunning
dykstraClifford
Dykstra
j-jonasJiri
Jonas
j-lisyJames
Lisy
shapleyJohn
Shapley
pshapleyPatricia
Shapley
zumdahl2Steven
Zumdahl
ksuslickKenneth
Suslick
jcoxJenny
Cox
sqdSean
Drummond
sheeleySarah
Sheeley
jsmaddenJoseph
Madden
cknight4Connie
Knight
schulzeHeather
Schulze
kbaumgarKeena
Finney
adkssnBeatrice
Adkisson
trabari1Katie
Trabaris
metclfKara
Metcalf
ljohnso2Lori
Johnson
lchenoweLeslie
Chenoweth
wdedoWolali
Dedo
spinnerDavid
Spinner
plblumPatricia
Simpson
stevens2Chad
Stevens
lsagekarLori
Sage-Karlson
bertholdDeborah
Berthold
kecarlsoKathryn
Carlson
sdesmondSerenity
Desmond
axelson2Jordan
Axelson
scbakerStephanie
Baker
pflotschPriscila
Falagan Lotsch
dgrayDanielle
Gray
thennes2Tom
Hennessey
holdaNancy
Holda
aibarrAlejandro
Ibarra
kimshSung Hoon
Kim
kocherg2Nikolai
Kocherginsky
philipk2Philip
Kocheril
legare2Stephanie
Legare
alewandoAgnieszka
Lewandowska
smccombiStuart
McCombie
jdm5Justin
McGlauchlen
egmooreEdwin
Moore
myerscouKathleen
Myerscough
snalla2Siva
Nalla
romanovaElena
Romanova
roubakhiStanislav
Rubakhin
shvedalxAlexander
Shved
asoudaAlexander
Soudakov
xywangXiying
Wang
kwilhelKaren
Wilhelmsen
wilkeyRandy
Wilkey
silongSilong
Zhang
schlembaMary
Schlembach
trimmellAshley
Trimmell
emccarr2Elise
McCarren
cmercierChristen
Mercier
atimpermAaron
Timperman
niesShuming
Nie
hshanHee-Sun
Han
mmgMutha
Gunasekera
kknightsKatriena
Knights
lisawLisa
Williamson
keinckKatie
Einck
kneef1Kate
Neef
txiang4Tiange
Xiang
j-hummelJohn
Hummel
i-paulIain
Paul
munjanjaLloyd
Munjanja
glnGayle
Nelsen
agerardAnna
Gerard
powerskaKimberly
Powers
lolshansLisa
Olshansky
miricaLiviu
Mirica
qingcao2Qing
Cao
lisa3Lisa
Johnson
tinalambTina
Lamb
baronpBaron
Peters
bransle2Sarah
Bransley
dylanmh2Dylan
Hamilton
raegansRaegan
Smith
apm8Angad
Mehta
leverittJohn
Leveritt
xingwXing
Wang
emillrEva
Miller
jmill24Jacqueline
Miller
jlbass2Julia
Bass
ramonarRamona
Rudzinski
tlcraneTracy
Crane
cejohnstCelia
Johnston
adlAmber
LaBau
cnsolomoCandice
Solomon-Strutz
mikaelbMikael
Backlund
jacksonnNick
Jackson