Parkin Protein Location, States, Structure, Mutations, And Substrates Transition

Location Of Parkin Protein

row	text
location	Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface
cytosol / source	Mainly localizes in the cytosol (PubMed:19029340, PubMed:19229105). https://www.uniprot.org/uniprotkb/O60260/entry#subcellular_location

States Of Parkin Protein

state	text
Resting condition	the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is sterically blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP.[6]
Activation	phosphorylation of serine Ser65 in Ubl by serine/threonine kinase, PINK1. Addition of a charged phosphate destabilises hydrophobic interactions between Ubl and neighbouring subregions, reducing autoinhibitory effects of this Nterminus domain.[13]
Activated status	disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface.[12] The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the Ub-thioester intermediate.
note	-folded in half (?)

Parkin Activation State Diagram

Autoinhibited Parkin
Ser65 pUb binding & UBL phosphorylation by PINK1
E2-Ub binding & Parkin~Ub charging
UBL
REP
RING2
RING0
RING1
IBR
pUb
E2
Ub
Gladkova, C. et al. Nature 2018
Trempe et al. Science 2013

Substitutions, Deletions, And Multiplications Map

label	values
domains	UBL, RING1, IBR, RING2
amino-acid positions	1, 76, 238, 293, 314, 377, 418, 449, 465
exon labels	EXON, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
deletion labels	Delta Ex1, Delta Ex2, Delta Ex3, Delta Ex4, Delta Ex5, Delta Ex6, Delta Ex7, Delta Ex8, Delta Ex7-8-9, Delta Ex10, Delta Ex11, Delta Ex12
row groups	Substitutions, Deletions, Multiplications

G12R
V15M
D18N
R33Q/STOP
P37L
R42P
T55I
V56E
E79X
A82E
D90N
Q100H
P153R
K161N
S167N
M192L/V
K211R/N
C212Y/G
R234Q
T240M/R
C253W/Y
R256C
D280N
G234R
R271S
N273S
R275W
C289G
Q311X
G328E
A339S
R334C
R366W
T351P
V380L
D394Y
T415N
G430D
C431F
C441R
P437L
W453STOP
W445STOP

Pathogenic Mutation Domain Map

UBL
linker
R0/UPD
R1
IBR
REP
R2
S65
C431
E2 binding site
p-Ser65-Ub binding site
Ub
Red - Loss-of-function mutations considered as pathogenic in Parkinson's disease
Black - Functional defects remain unclear
D Truban et al Journal of Parkinson's Disease 7 (2017) 13-29

R42H/CP
E79X
C253Y/F
G284R
R275W
C238Q/W
R334C/H
G328E
E409X
T445X
C431F

Structure Of Parkin & Mutation

Basic Protein Facts

Full length: aa 1-465,
Molecular Weight ~51.6 kDa
Accession number: NP_004553.2

Protein Sequence

MIVFVRFNSSHGFPVEVDSDTSIFQLKEVVAKR
QGVPADQLRVIFAGKELRNDWTVQNCDLDQQSI
VHIVQRPWRKGQEMNATGGDDPRNAAGGCEREP
QSLTRVDLSSSVLPGDSVGLAVILHTDSRKDSP
PAGSPAGRSIYNSFYVYCKGPCQRVQPGKLRVQ
CSTCRQATLTLTQGPSCWDDVLIPNRMSGECQS
PHCPGTSAEFFFKCGAHPTSDKETSVALHLIAT
NSRNITCITCTDVRSPVLVFQCNSRHVICLDCF
HLYCVTRLNDRQFVHDPQLGYSLPCVAGCPNSL
IKELHHFRILGEEQYNRYQQYGAEECVLQMGGV
LCPRPGCGAGLLPEPDQRKVTCEGGNGLGCGFA
FCRECKEAYHEGECSAVFEASGTTTQAYRVDER
AAEQARWEAASKETIKKTTKPCPRCHVPVEKNG
GCMHMKCPQPQCRLEWCWNCGCEWNRVCMGDHW
FDV

• A member of RING-between-RING (RBR) family of E3 ligases,

Structure / Functional Notes Table

row	N term	UBL	RING0	RING1	IBR	RING2	C term
domain header	N term	UBL (ubiquitin-like domain)	RING0	RING1	IBR	RING2	C term
function		Autoinhibition at basal condition			linker	전체 parkin 이 반으로 접혀 있으면서, RING1 과 RING2 가 서로 마주보고 있다.
structural description	an innovative structure resembling	an N-terminal Ublike	a unique Parkin domain-UPD	binding site for E2 Ub-conjugating enzyme		Contains the catalytic cysteine residue (Cys431) that cleaves Ub off
zinc-finger / substrate note	zinc-finger domain	domain (Ubl) for specific substrate recognition,				E2 and transiently binds it to E3 via a thioester bond
mutation note		Deletion of UBL domain with/without the linker has little effect on Parkin activity (2).	deletion of RING0 (lack of occlusion of C431 as described) causes increased C431 reactivity and Parkin autoubiquitination (3).	275는 여기있네. A second class of mutations, including Thr240Arg, affect residues in and around the E2 binding site and alter autoinhibition of RING1 by REP.[3]		Cys431Phe and Gly430Asp mutations impair ligase activity at the catalytic site and significantly reduce parkin function.
2015 Fiesel variants		p.R33Q; p.P37L; p.R42P	p.C150G; p.K161N; p.W183A; p.K211N	p.T240R; p.R256C; p.Y267H; p.R275W	p.G328E; p.R334C	p.T415N; p.G430D; p.C431F; p.C431S; p.F463A

over 90% of them are located in exons 2, 3, 4 and 7 ("hot" exons), (2017 Likhachev)
Mutations in hydrophobic residues of RING0:RING2 interface increase autoubiquitination (5).
Firstly, those clustered around Zn-coordinating residues on RING and IBR might compromise structural integrity and impair catalysis.[12]

Substrates And Function Of Parkin

Substrates (& function) of Parkin
functions in conjunction E2 enzymes UbcH7 (E2-640), UbcH8 (E2-644) and UbcH13/Uev1 (E2-664)
https://resources.rndsystems.com/pdfs/datasheets/k-

Uncertain Spans

location	text/status	reason
exon/deletion map	substitution labels and deletion bars	Dense labels are asset-primary; selected mutation labels are transcribed but should not be treated as complete.
mutation domain map	red/black mutation labels	Asset preserves full visual; OCR is unreliable for many mutation names.
protein sequence	MIVF...FDV sequence	Long sequence is visible and OCR-supported but should be checked once before structured KB use.
Fiesel variant row	p.C150G, p.K161N, p.W183A, p.K211N, p.R275W, p.G430D, signs such as +, ++, -	Very small symbols and variant IDs; image asset should be primary evidence.
substrates line	E2-640, E2-644, E2-664, truncated URL	Bottom section is cut off at the photo edge.